CN116261449A - Pharmaceutical composition for improved delivery of therapeutic lipophilic active substances - Google Patents

Pharmaceutical composition for improved delivery of therapeutic lipophilic active substances Download PDF

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CN116261449A
CN116261449A CN202180058382.1A CN202180058382A CN116261449A CN 116261449 A CN116261449 A CN 116261449A CN 202180058382 A CN202180058382 A CN 202180058382A CN 116261449 A CN116261449 A CN 116261449A
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sugar
oil
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拉斐尔·埃兹拉
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Kanak Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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Abstract

A solid water-dispersible composition of matter comprising at least one sugar, at least one polysaccharide and at least one surfactant, and at least one lipophilic Active Pharmaceutical Ingredient (API), the composition comprising more than one microparticles, each microparticle comprising more than one lipophilic nanosphere having an average size in the range of about 50-900nm, the at least one lipophilic API being contained in the microparticles and distributed inside and/or outside the lipophilic nanospheres in a predetermined ratio, thereby providing improved delivery of the at least one lipophilic API. A sugar particle comprising a porous sugar material and lipophilic nanospheres having an average size between about 50-900nm such that the lipophilic nanospheres are contained within the porous sugar material, the sugar particle comprising at least one edible sugar, at least one edible oil, at least one edible polysaccharide, at least one edible surfactant and at least one lipophilic API.

Description

Pharmaceutical composition for improved delivery of therapeutic lipophilic active substances
Technical Field
The present invention relates to compositions and methods for increasing the bioavailability of therapeutically active substances that are generally characterized as poorly water-soluble or lipophilic. The compositions and methods of the present invention are designed and adapted for use in a variety of drug delivery routes and are applicable to a wide range of poorly water-soluble drugs.
Background
Modern techniques for drug discovery, such as high throughput in vitro screening and combinatorial chemistry of receptor binding, have produced an increasing number of lipophilic, pharmacologically active compounds (APIs). The general rate limiting factor for oral absorption of these compounds is mainly their solubility/dissolution in the hydrophilic intestinal environment. Lipophilic drugs with low solubility and favorable permeability properties will be classified as class II or class IV compounds according to the biopharmaceutical classification system (Biopharmaceutical Classification System, BCS). Some notable examples are glibenclamide, bicalutamide, ezetimibe, aceclofenac, amphotericin B, and furosemide, acetazolamide, ritonavir, paclitaxel.
BCS class II and IV compounds generally have low oral bioavailability and therefore often fail to proceed to the later stages of development. These types of compounds are unlikely to be good clinical candidates unless accompanied by the development of specific formulation methods to overcome the problems of solubility or dissolution rate. Various schemes have been developed for this purpose, but are not without some major drawbacks.
Surfactants are routinely employed to increase the apparent water solubility of poorly soluble drugs. However, little is known about the effect of micelle solubilization on the intestinal permeability of lipophilic drugs. Many studies have shown that micelle formulations do not always retain their structure at the acidic pH of the stomach for the time required for their effective absorption. More recent studies have shown that surfactants may have an adverse effect on the solubility of a given API and its subsequent intestinal membrane permeability.
Another popular method of improving solubility relies on the use of cyclodextrin-based formulations. Cyclodextrins are crystalline, non-hygroscopic, cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. From a pharmaceutical point of view, cyclodextrins have gained widespread attention and use due to their ability to interact with poorly water-soluble drugs and to increase their water solubility. However, a review of the literature reveals that cyclodextrins are not entirely predictable, and their use may lead to counterintuitive results and even reduce the absorption of some APIs.
In summary, for many solubility enhancers there is a trade-off between their tendency to improve the solubility of lipophilic active substances and their tendency to have a negative effect on the corresponding intestinal membrane permeability of the same active substance. In other words, successful delivery methods depend on careful selection of the combination of solubility enhancers and other excipients, as well as their cumulative effect on the physicochemical and biological properties of the resulting formulation.
Thus, there is a clear incentive to develop new and more advanced formulations of lipophilic materials for overcoming the drawbacks of the solubility/permeability tradeoff. An even more challenging approach would be to propose a versatile and more inclusive method for improving the bioavailability of various types of lipophilic substances.
In academic and patent literature, including those applying nanotechnology, there are many publications describing certain types of oral formulations containing various lipophilic active substances. However, it appears that none of them is sufficiently inclusive and adaptable to be applicable to a wide range of pharmacologically relevant active substances and processes for the preparation of medicaments.
Some oral formulations containing lipophilic active substances are described in WO20035850, WO2015/171445, WO2016/147186, WO2016/135621 and WO2017/180954, among which are examples of cannabis or isolated and pure cannabinoids, all of which are known for their lipophilicity. More general examples of formulations with lipophilic APIs using various nanotechnologies are provided as solid formulations in WO19162951 and WO14176389, as liquid formulations in WO2013/108254, and in WO0245575 and WO03088894 together with active substances for specific uses in dentistry and cosmetics.
General description
The main focus of the present invention is to explore novel strategies for improving the permeability and bioavailability of highly lipophilic drugs. Over the past few years, drawbacks of conventional lipid-based formulations, such as physical instability, limited drug loading capacity, passive diffusion, active efflux in the GI tract, and extensive liver metabolism have been widely studied. New lipid formulations, and in particular nanostructured lipid carriers, have been developed to overcome the obstacles that cause poor bioavailability of lipophilic drugs.
Nanotechnology is an increasingly interesting area that opens new possibilities for the pharmaceutical industry. Nanotechnology is superior to conventional formulation techniques in terms of its ability to produce drugs with enhanced pharmacological properties, better quality and safety, and longer shelf life. Nanomaterials are now used as a basis for qualitative and quantitative production of old and new drugs with enhanced quality and new types of functions.
For poorly water-soluble substances or lipophilic active substances, nanodelivery systems using specific solubility enhancers such as nanoemulsions, dendrimers, nanomicelles, solid lipid nanoparticles offer a promising strategy for overall improvement of solubility, permeability, bioavailability and oral bioavailability. Some of these systems also provide for prolonged and targeted delivery of the active substance.
The fundamental advantage of nanocrystallization is to increase the substrate (substrate) surface area and dissolution rate. In the case of lipophilic substances, nanocrystallization may also increase saturation, solubility and reduce unstable absorption, thereby affecting transport of the lipophilic substance through the GI wall and improving its oral bioavailability. In addition, smaller particles are reported to be more readily absorbed by macrophages and thus provide higher deposition rates and better therapeutic index.
Nano-encapsulation of drugs/small molecules in nano-carriers is a very promising approach for nano-medical development. Modern drug encapsulation methods allow for the payload of drug molecules in nanovehicles, thereby reducing drug-related systemic toxicity. Another application is to target nano-carriers to specific tissues and organs and thus enhance the accumulation of encapsulated drugs at the diseased site. Nano-encapsulation can also prevent premature degradation of the drugs and thus increase their stability in circulation and tissues.
The present invention is part of such emerging technology. The present invention applies nanocrystallization techniques to prepare and manipulate materials on a new size scale and creates new structures with highly unique properties and a wide range of applications. To this end, the present invention provides a unique formulation approach to address specific problems of solubility and permeability associated with lipophilic APIs and to improve their in vivo bioavailability through oral and other non-invasive routes of administration. Importantly, as has been demonstrated so far, the formulation methods of the present invention are compatible with many kinds of lipophilic APIs and therefore have the potential for broad pharmacological applications.
The compositions of the present invention constitute solid particulate matter that is well dispersible in water. This quality itself constitutes a significant advantage in terms of stability, storage, operability and suitability for pharmaceutical use. Other properties of the compositions of the present invention are the specific composition and arrangement of their core components (i.e., sugar, polysaccharide, surfactant, and lipophilic nanospheres comprising an API in a pharmaceutically acceptable oil or oil carrier). This study shows that the oil and active substance can be distributed inside and outside the lipophilic nanospheres, which is why the characteristic of differential bioavailability of the composition of the present invention. The sugar, polysaccharide and surfactant provide a structure or porous network that entraps the lipophilic nanospheres. The structure or porosity of the network can be adjusted by the relative amounts of sugar, polysaccharide, surfactant and oil, and the size of the lipophilic nanospheres, which in turn affects the particulate structure and texture of the material as a whole. The advantages of this particular structure have been shown in the surprising feature of the compositions of the invention that they retain particle size, long-term stability and high loading capacity after dispersion in water.
Specific examples of core components of the composition of the present invention are trehalose as sugar, sucrose, mannitol, lactitol and lactose; maltodextrin and carboxymethyl cellulose (CMC) as polysaccharides; ammonium glycyrrhizate, pluronic F-127 and pluronic F-68 as surfactants. With respect to oil vehicles, the compositions of the present invention may use natural oils, such as oils rich in monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFAs) (e.g., omega-3 and omega-6), or synthetic oils, or mixtures thereof.
Thus, the compositions of the present invention are essentially mixed formulations that combine the advantages of lipid-based formulations and nanoparticles in terms of high loading, long-term stability, reproducibility, enhanced bioavailability and oral bioavailability, among other properties. All of these structural and functional properties of the compositions of the present invention have now been explored and exemplified.
More specifically, the key feature of maintaining nanoparticle size upon reconstitution of the powder composition in water was found to be consistent throughout various production processes, storage conditions and compositions of various sugars, oils and actives, as well as after fixation to a polyvinyl alcohol (PVA) film, and even after conversion of the composition into a mist form (examples 1-2, 7, 9).
First, the reproducible nanoscale features of lipophilic nanospheres are very surprising, especially given the known trend of nanoemulsions to increase particle size or fuse under a variety of conditions. Second, it is compatible with a variety of modes of administration that may involve drug dispersion and dilution. Third and most importantly, it demonstrates that the benefits of nanocrystallization can be maintained in the intestinal environment, with the expected results of higher solubility, permeability, and in situ bioavailabilty.
In summary, it can be said that the compositions of the present invention provide consistent loading, entrapment, storage and reconstitution capabilities of lipophilic active substances that remain after a variety of exposures, manipulations and conditions.
The high loading capacity feature was further addressed in a study showing that the composition of the present invention can be loaded with up to 90% -95% (w/w) of the total weight of the API in an oil vehicle, which does not destroy the core properties of maintaining nano-size in the reconstituted powder (example 3).
The chemical preservation characteristics of the active substances were addressed in a study showing that the composition of the present invention prevents degradation and oxidation of the active substances, even active substances sensitive to elevated temperatures, pro-oxidative substances and acidic pH, such as lycopene and fish oil (example 2).
Another important feature of the composition relates to the different distribution of APIs inside and outside the lipophilic nanospheres and the ability to increase the encapsulation capacity (examples 1.6-1.7). This feature is very useful in providing compositions of entrapped and non-entrapped APIs with differential bioavailability. This feature is further supported by the two-stage release profile (bi-phasic release profiles) of the active substance in the plasma and tissue found in vivo, which is characteristic of the composition of the invention (example 4).
The two-phase release mode provides an immediate burst of active release and a further prolonged active release. Animals exposed to the compositions of the invention showed a two-stage release profile in plasma and tissue, whereas animals exposed to a similar lipid composition showed only an immediate release profile. Due to limitations of the experimental timeframe, the exact duration and nature (intermittent or sustained) of the extended release profile remains to be determined in future studies.
It can be said that immediate release, prolonged release and potentially targeted release of the active substances are essential properties of the compositions of the invention themselves, since they originate from the specific composition and structure of their core components. In summary, these characteristics are reflected in the improved oral bioavailability of the present compositions relative to lipid forms having the same active substance.
The concept of bioavailability modulation is particularly applicable to active substances intended to achieve therapeutic objectives. The modified release composition provides selected characteristics of the time course and/or location of active release and has the potential to achieve a desired therapeutic result. The final product may also contain vehicles, excipients and various types of coatings that facilitate modified or targeted release of the active substance and provide the desired consistency and taste characteristics to achieve better compliance.
Importantly, the compositions of the present invention allow for modulation of the release profile by controlling the distribution of the API inside and outside the lipophilic nanospheres and thereby controlling the encapsulation capacity of the API. Encapsulation of the API depends on the amount and type of oil carrier and/or the amount and type of saccharides, polysaccharides, and surfactants. This can be further enhanced by removing the unencapsulated oil, for example with hexane.
In other words, the amounts and/or proportions of the oil carrier and other components determine the structure of the composition and the encapsulation capacity for lipophilic APIs, which in turn determine their differential availability. Thus, the loading, encapsulation capacity and bioavailability of the API can be adjusted by varying the amount and ratio of the core components of the composition.
Indeed, the compositions of the present invention may include various distributions and ratios of API and oil carrier inside or outside the lipophilic nanospheres, up to a degree of about a ratio between about 1:0 and 9:1, respectively, and specifically about a ratio between about 4:1, 7:3, 3:2, 1:1, 3:7, or 1:4, respectively.
Another important feature of the compositions of the present invention is the fact that they are provided in a solid or semi-solid water-dispersible form. In addition to the advantages in terms of stability and long-term storage, this property is also highly important when considering oral drug delivery. The oral route is the preferred route for drug delivery.
It has further been shown that the formulation method of the present invention can be applied to combinations of various types of saccharides, oil vehicles, oils and APIs (as a single active and active combination) (examples 1-11).
More specifically, it was demonstrated that the core properties of the compositions of the present invention were maintained during various preparation processes, in other words, the core properties were derived from the specific composition of the core component, rather than the preparation process (example 1.5).
Furthermore, uniformity and retention characteristics of particle size remained consistent after reconstitution of the composition into a polymer film (example 7) and in a solution with a high osmolarity (osmoticum) that mimics human skin conditions (example 1.8). The combination of these features makes the compositions of the present invention particularly attractive as a basis for a variety of skin (dermal) and surface (topical) formulations.
In terms of biological properties, improved bioavailability characteristics have been demonstrated in two independent experiments in animal models, wherein the compositions of the invention exhibit an advantageous pattern of immediate and prolonged release of the active substance into the circulation and tissues (example 4-example 5).
Furthermore, the composition of the invention itself exhibits the characteristic of improved bioavailability of the active substance, which is indicative of an effective amount of the remaining active substance available for absorption in the GI, and which is further enhanced in compositions incorporating enteric-coated (example 6). In other words, the compositions of the present invention were found to protect APIs from gastric degradation.
Still further, improved permeation characteristics through layers of human skin were demonstrated in a set of experiments showing that the compositions of the present invention have significantly enhanced permeation through layers 1 and 2 of the stratum corneum compared to the corresponding oil forms, and are associated with significantly higher rates of API penetration into deeper layers of the skin. (example 8).
The particular adaptability and compatibility characteristics of the compositions of the present invention with various non-invasive modes of administration other than oral have been demonstrated at present by incorporating reconstituted powders into polymeric sublingual, dermal patches (example 7) and further converting them into a mist form in an inhaler or nebulizer (example 9); all this while maintaining the core properties of nanoparticle size.
More recent experiments with lipophilic antibiotics have shown that the powder composition of the present invention can enhance the efficacy of known lipophilic antibiotics against pathogenic bacteria, including highly resistant strains. Furthermore, due to the unique properties of small particle size and improved solubility, the powder compositions of the present invention may have the ability to disrupt and/or enhance the permeation of antibiotic actives through microbial biofilms (example 10).
In summary, the present study shows that the powder composition of the present invention can protect the API against various harmful exposures (such as during production and storage and acidic conditions in the GI) and further that the API can be presented to the circulation and organization in a more bioavailable and bioavailable form.
Thus, the formulation methods presented herein provide a considerable degree of flexibility and applicability to various types of lipophilic APIs, or in other words, to a number of therapeutic agents belonging to the BCS class II and class IV compound groups. Many drugs that are useful as enzyme inhibitors, receptor antagonists and agonists, proton pump and ion channel inhibitors, inhibitors and reuptake inhibitors are classified as BCS class II and class IV.
Specific applications for incorporating lipophilic APIs into micronized sugar particles of the present invention are provided. Specifically, the present invention provides a smooth finely granulated sugar powder (finely granulated sugar powder) which is itself a composite particulate material made of a sugar crystalline matrix and embedded lipophilic nanospheres. This structure imparts desirable sugar characteristics (e.g., taste, small crystals, large surface area, high solubility, mechanical and thermodynamic stability, etc.) and the ability to entrap lipophilic APIs to the composite (example 10). This application is particularly advantageous for certain types of actives where taste masking is required.
Finally, the powder compositions of the present invention are associated with higher loadings, higher encapsulation capacity, higher stability, modified release and improved oral bioavailability and bioavailability properties of the active, which significantly exceed those associated with similar lipid-based compositions; this uses the lowest concentration of surfactant. Furthermore, in contrast to lipid-based compositions in which the excipient exhibits limited exertion, the compositions of the present invention allow the use of a full range of excipients. All of these make the compositions of the present invention a promising approach to improving the in vivo properties of lipophilic APIs, making them highly relevant for pharmaceutical and medical applications.
Brief Description of Drawings
For a better understanding of the subject matter disclosed herein and to illustrate how the subject matter disclosed herein may be carried into practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings.
Figure 1 illustrates the characteristic particle size retention characteristics of the powder composition of the present invention. The figures show powder compositions comprising cannabinoids (THC or CBD) stored at 45 ℃ (oven) for 1 day, 35 days, 54 days, 72 days and 82 days (3 months being equivalent to 24 months at RT).
Figure 2 illustrates the characteristics of protecting lipophilic active substances conferred by the powder composition of the present invention. The figure shows the total TOTOX (oxidation state) values of fish oil (dotted line) and a powder composition comprising fish oil (solid line). Fish oils are sensitive to oxidation. The graph shows significantly lower levels of primary and secondary oxidation products in fish oils formulated into powder compositions starting on day 0 and up to day 14.
Figures 3A-3B illustrate the advantages of the improved oral delivery and rapid release of API in plasma characteristic of the compositions of the invention (LL-P) compared to lipid-based compositions (LL-oil) containing CBD (3A) and THC (3B) as disclosed after a single oral dose administration in a rat model.
FIGS. 4A-4B reproduce these advantages in controlled studies comparing powder compositions (LL-P) containing CBD (4A) and THC (4B) with lipid-based compositions (LL-oil) containing the same APIs. The figure shows a specific two-phase active release profile in plasma characteristic of the composition of the invention.
Figures 5A-5D show that the advantages of improved oral bioavailability are reproduced in animal tissues administered a powder composition containing THC and CBD (LL-P) and a lipid-based composition containing the same API (LL-oil). The figure shows a two-phase active release profile in the liver and brain characteristic of the composition of the invention.
Figure 6 shows that the advantages of improved oral delivery and bioavailability apply to a wide range of lipophilic active substances. The graph shows the active release profile of a powdered vitamin D3 composition (solid line) in plasma compared to a similar lipid composition (dashed line) after single oral dose administration in a rat model. The powder composition shows a 2-fold increase in vitamin D3 concentration relative to the lipid composition.
Figure 7 illustrates the characteristics of enhanced bioavailability (GI digestion degree) characteristic of the compositions of the present invention using a semi-dynamic in vitro digestion model. The figure shows the enhanced bioavailability of the two APIs (thymol and carvacrol) found in oregano of the powder composition (P) compared to the corresponding oil form (O) for each API and total API.
Figures 8A-8D further extend the advantages of improved bioavailability using semi-dynamic models. The figure shows that the protective effect and bioavailability of the powder composition can also be enhanced by enteric capsules (solid line) compared to the powder composition alone (dotted line) and the oil-based composition (dotted line). The figures relate to the bioavailability of total thymol and carvacrol (a), carvacrol (B) and thymol (C) at the end of the gastric phase (gastro-phase), and the bioavailability of total thymol and carvacrol (D) in a powder composition with enteric capsules during the gastric phase and duodenal phase (duodenonal phase).
Fig. 9 illustrates the advantage of improved permeability through the full thickness of human skin as disclosed in the ex vivo model. The figure shows that the penetration of vitamin a in the powder composition is increased by a factor of 6 compared to a lipid composition containing the same API.
Fig. 10A-10C show similar experiments regarding the permeability of CBD in powder and lipid compositions through stratum corneum outermost layer 1 (a), stratum corneum layer 2 (B) and significantly higher cumulative transport of CBD into deeper layers of the skin, i.e. overall (C).
Fig. 11A-11B are SEM images (scanning electron microscope) at x1K (a) and x5K (B) magnification showing sugar particles containing cocoa butter (Theobroma oil) having a characteristic smooth, finely particulated texture and a size in the range of 20-50 μm.
Fig. 12A-12D illustrate the complex nature of the sugar particles of the present invention. The figure is a frozen TEM image (frozen transmission electron microscope) showing lipophilic nanospheres of average size of 80-150nm embedded in sugar particles.
Detailed description of the embodiments
It is to be understood that this invention is not limited to the particular methods and experimental conditions described herein, and that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
Effective oral delivery of drugs is highly affected by water solubility and the inherent dissolution rate. Dissolution is the main rate limiting step in the absorption of BCS class II or IV drugs, with additional factors such as hepatic first pass metabolism, drug excretion from P-gp, intestinal intracellular metabolism, and chemical and enzymatic degradation.
When poorly water-soluble drugs enter the GI, a series of events limit their absorption: first, bile secretions in the upper part of the GI play a role in the dissolution and emulsification of such drugs through the formation of micelles, thereby presenting the absorption membrane of intestinal cells in a more bioavailable form. However, the capabilities of this process are very limited and variable.
Second, the unstirred aqueous layer (unstirred water layer, UWL) separating the brush border of intestinal cells (atypical membrane) from the bulk of the intestinal fluid is the primary hydrophilic barrier for lipophilic compound absorption.
Third, in intestinal cells, there is a biochemical barrier that affects drug absorption. The CYP3A4 (CYP 3A 4) enzyme in the intestinal endoplasmic reticulum is responsible for the major part of drug metabolism in the intestinal wall. Studies have shown that it is a major obstacle to lipophilic drug absorption.
Fourth, drug efflux transporters, such as P-gp, located at the apical intestinal membrane are also responsible for poor oral bioavailability of various drugs (e.g., digoxin, paclitaxel, doxorubicin, atorvastatin, etc.). The apical P-gp efflux pump is the most studied transporter, reducing drug absorption by transporting drug from intestinal cells back into the intestine. There is a link between the CYP3A4 enzyme and P-gp activity, which work synergistically to reduce the bioavailability of lipophilic drugs.
Fifth, after intestinal intracellular metabolism, P-gp efflux, and before reaching the systemic circulation, the drug is transferred to the liver where it is exposed to various metabolic enzymes. This first pass liver metabolism is another significant barrier to the absorption of lipophilic drugs (e.g., beta blockers, calcium channel blockers, and others).
In view of the above pharmacokinetic and pharmacodynamic barriers, there is an urgent need to design novel formulations to increase the oral bioavailability of poorly water-soluble or lipophilic drugs.
Many researchers and pharmaceutical industries are developing various delivery systems based on different nanoemulsion preparation methods. In general, one of the major drawbacks of nanoemulsions is their relative instability in terms of particle size over time. In particular nanoemulsions in the form of solid powders, are known for their lack of uniformity of particle size and in particular after reconstitution in water. In addition, there is a general trend to increase particle size due to fusion of particles under various conditions.
The lack of increased particle size and uniformity causes significant variability in the absorption of the entrapped material in the nanoparticles, as well as poor oral bioavailability. Larger particles have a smaller surface area and therefore are less absorbed in plasma and tissue. Thus, despite the potential of nanoemulsion technology, there are significant drawbacks to incorporating it into the pharmaceutical industry.
The present invention has demonstrated that these difficulties are overcome with a lipophilic API nanocrystallized powder composition that maintains the loading, encapsulation and storage potential, and improved oral bioavailability properties while readily dispersing in water.
In the broadest sense, the compositions of the present invention may be expressed as solid water-dispersible compositions of lipophilic Active Pharmaceutical Ingredients (APIs). Importantly, the compositions of the present invention are particularly advantageous for long term storage, preservation, oral delivery, and the like, due to the solid or semi-solid composition and ability to produce a homogeneous dispersion in water.
In many embodiments, the compositions of the present invention are provided in the form of a water-dispersible powder.
As for an active substance, the term "active pharmaceutical ingredient (active pharmaceutical ingredient, API)" refers herein to any substance falling under the definition of WHO, i.e. a substance intended to provide pharmacological activity or otherwise have a direct effect in the diagnosis, cure, alleviation, treatment or prevention of a disease, or a direct effect in restoring, correcting or altering the physiological function of a human.
In many embodiments, the compositions of the invention comprise one or more lipophilic APIs dissolved in an oil carrier or pharmaceutically acceptable oil.
The term "lipophilic API" requires additional attention. Lipophilicity refers to the ability of a compound to dissolve in fats, oils, lipids, and nonpolar solvents. Lipophilic, hydrophobic and nonpolar describe the same trend, although they are not synonymous. The lipophilicity of uncharged molecules can be estimated experimentally by measuring partition coefficients (logP) in a water/oil two-phase system. For molecules that are weak acids or weak bases, the measurement must further take into account the pH at which most of the material remains uncharged.
Positive values of logP indicate higher concentrations in the lipid phase.
Thus, in many embodiments, the present invention is applicable to non-charged or weakly charged lipophilic APIs having partition coefficients (logps) greater than 0.
More specifically, the invention is applicable to any lipophilic API having logP within the following ranges: 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-16, 16-17, 17-18, 18-19, 19-20 or more.
The term "lipophilic API" further relates to certain classes of BCS drugs that are related by their solubility and permeability properties to four known classes: class I compounds with higher solubility and permeability; class II with lower solubility but higher permeability; class III with higher solubility but lower permeability; and the lowest count class IV compound with solubility and permeability index.
Thus, in many embodiments, the compositions of the present invention are particularly useful for BCS class II and class IV compounds.
In some embodiments, the compositions of the present invention are suitable for BCS class II compounds.
From another point of view, the composition of the present invention may be considered as a composite material (composition matter) comprising more than one microparticles, each microparticle comprising more than one lipophilic nanosphere having an average size in the range of about 50nm to about 900nm, at least one lipophilic API being contained in the microparticles and distributed inside and/or outside the lipophilic nanospheres in a predetermined ratio, thereby providing improved delivery of the at least one lipophilic API.
In other words, the compositions of the present invention are solid particulate matter comprising particles of micrometer scale, or particles having an average size in the range of between about 10-900 μm, or more specifically in the range of 10-100 μm, 100-200 μm, 200-300 μm, 300-400 μm, 400-500 μm, 500-600 μm, 600-700 μm, 700-800 μm and 800-900 μm.
In certain embodiments, the powder of the present invention may comprise particles having an average size in the range of between about 10 μm and about 300 μm, or more specifically, an average size in the range of 10-50 μm, 50-100 μm, 100-150 μm, 150-200 μm, and 250-300 μm.
Microparticles of the compositions of the present invention are themselves composite materials comprising lipophilic nanospheres having an average size in the range of about 50-900nm, and more specifically in the range of about 50-100nm, 100-150nm, 150-200nm, 200-250nm, 250-300nm, 300-350nm, 350-400nm, 400-450nm, 450-500nm, 500-550nm, 550-600nm, 650-700nm, 700-750nm, 750-800nm, 800-850nm, 850-900nm and 900-1000nm (average size is average diameter herein).
The size or diameter of the lipophilic nanospheres can be measured by DLS (dynamic light scattering) after reconstitution of the powder composition in water, which is exemplified by the present invention.
In many embodiments, the size of the microparticles is related to the size of the lipophilic nanospheres, meaning that the size of the lipophilic nanospheres determines the size of the microparticles.
The above means that the lipophilic nanospheres are substantially embedded in the microparticles. It is also meant that such a composite material has a certain porosity or arrangement that allows accommodation of the nanospheres. The present invention exemplifies these two features. They are further reflected in the load and encapsulation capacity characteristic of the compositions of the present invention (see below).
An important feature of the present invention is that the shape and size of the lipophilic nanospheres are substantially maintained after dispersion in water. In other words, due to the specific composition and structure of the composite material, the average size of the nanospheres is maintained under various conditions such as lyophilization, long term storage, immobilization, and release from a matrix or film such as PVA, etc. The term "substantially maintained" means herein a deviation of 1% -5%, 5% -10%, 10% -15%, 15% -20% or up to 25% of the average diameter before and after operation or exposure to certain conditions.
An important feature of the composition of the present invention is the distribution of lipophilic APIs inside and outside the lipophilic nanospheres. This feature is responsible for the characteristic immediate and/or prolonged delivery or release properties of the active substances of the compositions of the invention.
In many embodiments, the lipophilic API may be distributed inside or outside the lipophilic nanospheres in a ratio of between about 1:0 and 9:1, respectively.
In certain embodiments, the lipophilic API may be distributed inside or outside the lipophilic nanospheres in a ratio between about 4:1, 7:3, 3:2, respectively, meaning that they are present in excess inside the lipophilic nanospheres.
In other embodiments, the lipophilic API may be distributed inside or outside the lipophilic nanospheres in a ratio between about 3:7 or 1:4, respectively, meaning that they are present in excess outside the lipophilic nanospheres.
In yet other embodiments, the lipophilic API may be distributed inside or outside the lipophilic nanospheres in a ratio of about 1:1, meaning that they are present inside and outside the lipophilic nanospheres in approximately equal proportions.
The same characteristics can also be expressed in terms of the encapsulation capacity of the lipophilic API in the composition. The term "encapsulation capacity" refers to the amount or proportion of lipophilic API embedded within a particulate material or the entire powder composition.
In many embodiments, the compositions of the present invention may have a lipophilic API encapsulation capacity of up to at least about 80% (w/w) relative to the total weight, or more specifically up to at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97% and 98% (w/w) relative to the total weight, or an encapsulation capacity in the range of about 50% -98%, 60% -98%, 70% -98%, 80% -98% and 90% -98% (w/w).
This feature is also related to the loading capacity of the lipophilic API on the composition. The term "loading capacity" refers to the amount or proportion of lipophilic API loaded onto the powder composition.
In many embodiments, the compositions of the present invention may have a loading capacity of the lipophilic API of up to at least about 80% (w/w) relative to the total weight, or more specifically up to at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97% and 98% (w/w), or in the range of about 50% -98%, 60% -98%, 70% -98%, 80% -98% and 90% -98% (w/w) relative to the total weight.
Another important feature that characterizes the compositions of the present invention is long-term stability or extended shelf life. This feature encompasses structural, chemical and functional stability herein. In this case, the structural stability is reflected in the ability of the nanospheres to retain particle size after reconstitution in water. Chemical stability reflects protection against degradation and oxidation under conditions such as temperature, light and acidic pH. Functional stability is reflected in the maintenance of the properties of immediate and prolonged active substance release.
In many embodiments, the compositions of the present invention may have long term stability at room temperature of about at least about 1 year, or more specifically, up to about 6 months, 1 year, 2 years, 3 years, 4 years, 5 years at room temperature.
For the core component, in general, the composition of the invention comprises at least one sugar, at least one polysaccharide and at least one surfactant, and at least one lipophilic API.
In many embodiments, the lipophilic API may be dissolved in at least one oil carrier or pharmaceutically acceptable oil.
In other embodiments the lipophilic API itself may constitute an oily substance or a pharmaceutically acceptable oil.
Examples of these two types of active materials have been provided by the present invention (examples 1-9).
As already noted, the oil and other core components are mainly responsible for the alignment and porosity of the composite material and, together with the oil component, affect the characteristics of particle size retention, loading and encapsulation capacity characteristic of the composition of the invention.
The term "pharmaceutically acceptable oil" is used herein to encompass any oil that is generally safe, non-toxic or biologically undesirable and acceptable for use in humans. The oils contained in the compositions of the present invention may be broadly characterized as non-toxic oils for the food and pharmaceutical industries, as regulated by the FDA or EMA, or classified as GRAS (generally recognized as safe).
In many embodiments, the pharmaceutically acceptable oil may be obtained from a plant or animal source, a synthetic oil or fat, or a mixture thereof.
In many embodiments, the pharmaceutically acceptable oil may be a natural oil, a synthetic oil, a modified natural oil, or a combination thereof.
In certain embodiments, the pharmaceutically acceptable oil may be selected from the group consisting of acyl glycerols, monoacylglycerols (MAG), diacylglycerols (DAG) and Triacylglycerols (TAG), medium Chain Triglycerides (MCT), long Chain Triglycerides (LCT), saturated or unsaturated fatty acids.
In many embodiments, the compositions of the present invention may comprise a pharmaceutically acceptable oil from a plant or animal source. For example, an oil comprising a substantial proportion of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) would be advantageous in terms of additional health benefits.
In certain embodiments, the pharmaceutically acceptable oil may be selected from the group of omega oils, such as omega 3, omega 6, omega 7, and omega 10, or combinations thereof. Omega-3 and omega-6 fatty acids play a vital role in brain function, normal growth and development. Omega-6 type helps to stimulate skin and hair growth, maintain bone health, regulate metabolism and the reproductive system.
In certain embodiments, the pharmaceutically acceptable oil may be industrial hemp oil (hemp oil), alone or in combination with other oils. Industrial hemp oil is helpful for skin regeneration.
Thus, from a broader perspective, the compositions of the invention may comprise any pharmaceutically acceptable type of vegetable oil, animal oil or fat or essential oil. A non-limiting list of related oils is provided in appendix a.
For saccharides, saccharides suitable for use in the compositions of the present invention may be broadly characterized as short chain carbohydrates and sugar alcohols, and more particularly oligosaccharides, disaccharides, monosaccharides and polyols. Sugar is safe and widely used in the pharmaceutical industry. The sugar may be of natural origin or synthetic origin.
In many embodiments, the sugar may be selected from trehalose, sucrose, mannitol, lactitol and lactose.
In other embodiments, the sugar may be xylitol, sorbitol, maltitol.
Related polysaccharides can be broadly characterized as polysaccharides suitable for use in the pharmaceutical industry and generally considered safe. They may be natural polysaccharides and/or synthetic polysaccharides. Specific examples of natural polysaccharides are levan found in many cereals and galactan found in vegetables, and additionally methylcellulose, carboxymethylcellulose and hydroxypropyl methylcellulose, and also pectin, starch, alginates (alginates). A non-limiting list of related polysaccharides is provided in appendix a.
In many embodiments, the polysaccharide may be selected from maltodextrin and carboxymethylcellulose (CMC).
Related surfactants can be broadly characterized as non-toxic surfactants suitable for use in the pharmaceutical industry, and in particular, nonionic and anionic surfactants. Examples of anionic surfactants include (a) carboxylates: alkyl carboxylate-fatty acid salt; carboxylate fluorosurfactant, (b) sulfate: alkyl sulfates (e.g., sodium lauryl sulfate); alkyl ether sulfates (e.g., sodium lauryl ether sulfate), (c) sulfonates: a docusate (e.g., dioctyl sodium sulfosuccinate); alkylbenzene sulfonate, (d) phosphate: alkyl aryl ether phosphate esters; alkyl ether phosphates. Sodium lauryl sulfate BP (mixture of sodium alkyl sulfates, mainly sodium lauryl sulfate, C 12 H 25 SO 4 – Na + ). Nonionic surfactants may include polyol esters, polyoxyethylene esters, poloxamers. Polyol esters include glycol esters and glycerol esters and sorbitan derivatives. Fatty acid esters of sorbitan (Span) and ethoxylated derivatives thereof (Tween, e.g., tween 20 or Tween 80) are commonly used nonionic surfactants. A non-limiting list of relevant surfactants (or emulsifiers) is provided in appendix a.
The most frequently used surfactants in the pharmaceutical industry are polysorbate 20 and polysorbate 80 and poloxamer 188 at concentrations ranging from 0.001% to 0.1%.
In many embodiments, the surfactant may be selected from the group consisting of ammonium glycyrrhizate, pluronic F-127, and pluronic F-68.
In other embodiments, the surfactant may be selected from monoglycerides, diglycerides, glycolipids, lecithins, fatty alcohols, fatty acids, or mixtures thereof.
In other embodiments, the surfactant may be a sucrose fatty acid ester (sugar ester).
In many embodiments, the compositions of the present invention may comprise any combination of the above components, as well as more than one agent from the above group.
For APIs, as already noted, the compositions of the present invention encompass a wide range of active substances. Related APIs can be broadly classified based on their function, such as enzyme inhibitors, receptor antagonists, agonists, proton pumps and ion channel inhibitors and/or reuptake inhibitors. Examples of lipophilic APIs belonging to these groups are Angiotensin Converting Enzyme (ACE) inhibitors for the treatment of hypertension, selective 5-hydroxytryptamine reuptake inhibitors (SSRI) for a wide range of psychiatric contexts, and Retinoid X Receptor (RXR) agonists for the treatment of cancer, all of which are highly lipophilic.
Alternatively, related APIs may be categorized as antibiotics, antifungals, antivirals, neuroleptics, analgesics, hormones, anti-inflammatory agents, non-steroidal anti-inflammatory agents, antirheumatic agents, anticoagulants, beta-blockers, diuretics, antihypertensives, anti-atherosclerosis and antidiabetics, anti-asthmatics, decongestants, cold agents. Examples of lipophilic drugs from these groups are synthetic opioids such as pethidine, non-steroidal anti-inflammatory drugs (NSAIDs) such as flurbiprofen and ibuprofen, antibiotics such as highly lipophilic rifampin, and statins such as tolvastatin, simvastatin, lovastatin.
In other words, the primary criteria for selecting candidate APIs for the compositions of the present invention is lipophilicity. Thus, the candidate lipophilic APIs may be from one or more of the general drug classes defined by the FDA. A non-limiting list of relevant drug groups is provided in appendix a.
It should be noted that the compositions of the present invention are also applicable to other lipophilic actives such as nutraceuticals (nutraceuticals), vitamins, dietary supplements, nutrients, antioxidants and others, which may be incorporated into the composition along with the lipophilic API.
As already noted, in many embodiments, the pharmaceutically acceptable oil itself may be characterized as a nutraceutical, a vitamin, a dietary supplement, a nutrient, and an antioxidant. Examples of such oils are omega oils and fish oils as exemplified in the present application.
More generally, in many embodiments, the lipophilic API may constitute between about 10% to about 98% (w/w) of the present compositions, or more specifically about 10% -20%, 20% -30%, 30% -40%, 40% -50%, 50% -60%, 60% -70%, 70% -80%, 80% -90% and 90% -98% (w/w) of the present compositions, or up to about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% and 98% (w/w) of the present compositions.
On the other hand, in many embodiments, the sugar may constitute between about 10% to about 90% (w/w) of the present composition, or more specifically about 10% -20%, 20% -30%, 30% -40%, 40% -50%, 50% -60%, 60% -70%, 70% -80% and 80% -90% (w/w) of the present composition, or up to about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% (w/w) of the present composition.
Furthermore, in many embodiments, the compositions of the present invention may also comprise carriers, excipients and additives for the purpose of color, taste and specific consistency. The term "carrier and excipient" is herein intended to encompass any inactive material that serves as a vehicle or medium for the API and oil contained in the composition.
Another important feature of the compositions of the present invention is the ability to provide improved delivery of lipophilic APIs. The term "improved delivery" is herein intended to encompass improved drug solubility, drug absorption or drug release by any pharmacokinetic or pharmacodynamic parameter to provide improved oral, topical, dermal and transdermal bioavailability or drug delivery via any other route.
The concept of improved delivery is based on the discovery of excellent pharmacokinetic and pharmacodynamic properties of the present compositions in plasma and tissues after oral administration (example 4-example 5) and topical application (example 8).
The term 'improved' is herein intended to cover variations in the range of about 5% -10%, 10% -15%, 15% -20%, 20% -25%, 25% -30%, 30% -35%, 35% -40%, 45% -50%, 50% -55%, 55% -60%, 60% -65%, 65% -70%, 70% -75%, 75% -80%, 80% -85%, 85% -90%, 90% -95%, 95% -100% relative to an oil form containing the same active substance, or up to 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold relative to an oil form containing the same active substance.
The term also encompasses any advantageous change in the mode of drug release, permeability or absorption, including the ability to modulate such modes, such as those disclosed in the compositions of the present invention.
Thus, in many embodiments, the compositions of the invention may provide immediate release of the lipophilic API to one or more portions of the GI tract, plasma, or one or more tissues.
The term "immediate release" means that the lipophilic API can be measured in the GI or plasma in a relatively short period of time, such as after 1min, 10min, 20min, 30min, 40min, 50min, 60min from oral administration. It also means burst or transient release of API in GI or plasma. The term also applies to the level of API in an organ or tissue (albeit with a slight delay), such as the level of API in an organ or tissue within 10min, 20min, 30min, 40min, 50min, 60min, 70min, 80min, 90min after oral administration by oral or any other route.
In other embodiments, the compositions of the invention may provide for prolonged release of the lipophilic API to a portion of the GI tract, plasma, and/or tissue.
The term "prolonged release" means that the active substance is measured with a certain hysteresis in the GI, plasma and tissue, such as after 30min, 60min, 90min, 120min from the start of oral administration, and for 2h, 3h, 4h, 5h, 6h, 7h, 8h and longer in the GI, plasma and tissue after oral administration.
The term also encompasses situations where the API continues to increase, or increases and reaches a plateau, and increases in one or more short bursts.
In other embodiments, the compositions of the invention may provide two-stage release, including immediate release and prolonged release of the lipophilic API to a portion of the GI tract, plasma, and/or tissue.
In certain embodiments, the compositions of the present invention provide for immediate release and/or prolonged release of the lipophilic API to one or more tissues of the Central Nervous System (CNS).
In certain embodiments, the compositions of the invention provide immediate release and/or prolonged release of the lipophilic API to the lymphoid tissue, one or more parts of the GI, and/or liver.
The improved delivery profile of the active substance is directly related to improved oral bioavailability. Thus, in many embodiments, the compositions of the present invention provide improved oral bioavailability of lipophilic APIs compared to similar oil forms. This feature has been illustrated for various types of compositions of the present invention.
Furthermore, in many embodiments, the compositions of the present invention provide improved bioavailability of lipophilic materials compared to similar oil forms. The term "biological accessibility" refers herein to the amount of API released in the GI tract and made available for absorption (into the blood stream), which also depends on the digestive conversion of the API to a substance to be absorbed, absorption into intestinal epithelial cells, and pre-systemic metabolism (pre-systemic metabolism), intestinal metabolism and hepatic metabolism.
In many embodiments, the compositions of the invention may also provide improved penetration of the lipophilic API into one or more portions or one or more tissues of the GI tract, as compared to a similar oil form.
Modulation of pharmaceutical biological properties such as drug delivery, bioavailability, and penetration can have a significant impact on the potential to achieve desired therapeutic results or better patient compliance.
More specifically, modulation of these properties can have a significant impact on therapeutically effective dosing, frequency of administration, and overall drug regimen.
The term "therapeutically effective amount" (also referred to as a pharmacologically, pharmaceutically or physiologically effective amount) broadly refers to the amount of API required to provide a desired level of physiological or clinically measurable response. Similar terms are "therapeutic dose" or "therapeutically effective dose" refer to a dose of an API in a pharmaceutical composition or dosage form that produces an improvement/alleviation of at least one symptom of a disorder, disease, or condition.
The formulation methods of the present invention provide excellent flexibility for therapeutically effective dosages, as well as the ability to encapsulate and load various API amounts. Due to the wide range of applicability of the present compositions to various types of APIs, an effective amount can be expressed in terms of a ratio.
In many embodiments, the therapeutically effective amount of lipophilic API and other actives included in the compositions may range between about 10% to about 98% (w/w) of the composition, or more specifically between about 10% -20%, 20% -30%, 30% -40%, 40% -50%, 50% -60%, 60% -70%, 70% -80%, 80% -90% and 90% -98% (w/w) of the composition, or up to about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% and 98% (w/w) of the composition.
A therapeutically effective amount or dose may also be expressed as a dose of each single dosage form and/or API per administration, and also expressed as a daily or weekly dose meaning more than one administration.
For therapeutic effects, improvement or alleviation of symptoms of a disorder or condition may be assessed by one or more of the following parameters: the type and/or number of symptoms, the severity of the symptoms, the frequency of the symptoms, the particular group of symptoms (partial symptoms), and/or the overall appearance of the symptoms in the subject or group of subjects. The effect may also be expressed as a reduction in severity level, e.g., a reduction in symptoms by up to about 5%, 10%, 15%, 20%, 25%, 50%, 75%, 100% or complete elimination of symptoms.
These parameters also depend on specific APIs and patient-specific factors, such as pre-existing conditions, compliance, etc. They mean estimates based on individuals (individuals) and on populations (clinical trials).
The mechanism by which the compositions of the present invention exert improved oral bioavailability remains to be discovered. One may assume that the particular combination and structure of core components and particles may contribute to one or more of the following mechanisms:
the lipophilic component may aid in bile secretion and emulsification of the API. Various lipids have been shown to induce bile secretion in the upper GI and enhance emulsification-dependent drug absorption, thereby improving bioavailability.
Nanospheres can facilitate the passage of APIs across UWL. It has been shown that the nano-particle size improves the surface area and thus the dissolution of hydrophobic drugs in UWL.
Encapsulation into nanoparticles protects the API from enzymatic degradation. It has been shown that the encapsulated drug is less exposed to enzymatic degradation during the absorption process and can stay in the intestinal lumen of the body for a longer period of time.
It has been shown that certain lipid excipients and surfactants are capable of inhibiting P-gp mediated drug efflux and have the potential to alter the pharmacokinetic profile of the API in vivo.
Certain lipids and oils may also stimulate lymphatic transport, providing a way to bypass liver metabolism. Thus, for drugs that are heavily metabolized on the first pass through the liver, the lymphatic pathway may provide rescue and significantly enhance their bioavailability.
Thus, the platform presented in the present invention can provide a comprehensive and inclusive approach to design and develop novel formulations of lipophilic drugs with improved quality of bioavailability, tissue distribution, and short-term and long-term effects.
The compositions of the present invention may also be characterized by the mode of administration. In many embodiments, the compositions of the present invention may be suitable for oral, sublingual or buccal administration.
In other embodiments, the compositions of the present invention may be suitable for rectal, topical, dermal or transdermal administration.
However, in other embodiments, the compositions of the present invention may be suitable for inhalation or nebulization. These specific applications have been recently exemplified.
In many embodiments, the compositions may comprise coatings and packaged forms that facilitate long-term storage, stability, and other properties. The use of enteric capsules and their role in enhancing the bioavailability of the compositions of the present invention have now been exemplified.
In many embodiments, the composition may comprise one or more carriers and/or one or more coatings.
Gastric-resistant and controlled release coatings are particularly suitable for oral dosage forms. Such coatings may be achieved by a variety of known techniques, such as the use of poly (meth) acrylates or layering. Well known examples of poly (meth) acrylate coatings are
Figure BDA0004113560050000221
In addition to increasing the effectiveness of the active, the poly (meth) acrylate coating also provides protection from external influences (moisture) or provides taste/odor masking to increase compliance.
Layering encompasses herein a range of techniques using substances applied in layers in the form of solutions, suspensions (suspension/solution layering) or powders (dry powder layering). Various characteristics can be achieved by using supplementary materials.
It should be noted that certain types of coatings may also enhance targeting to specific tissues and organs.
In other words, one of the advantages of the present technology is its ability to provide flexible products that can accommodate a variety of pharmaceutical technologies.
All of the above further apply to the methods, dosage forms and various other applications for the pharmaceutical industry of the present invention.
More specifically, it is a further object of the present invention to provide a dosage form comprising a therapeutically effective amount of a composition according to the above.
In many embodiments, the oral dosage form of the present invention may be provided in the form of a tablet or capsule.
Thus, in many embodiments, the oral dosage form of the present invention may comprise a coating, shell, or capsule.
As already noted, in many embodiments, the coating, shell, or capsule may facilitate prolonged delivery of the lipophilic API.
In many embodiments, the coating, shell, or capsule contributes to the enhanced bioavailability of the lipophilic API.
In many embodiments, the dosage form may contain additional vehicles, excipients, and other additives for color, taste, and specific consistency purposes.
In many embodiments, the dosage form may be adapted for oral, sublingual, buccal, rectal, topical, dermal or transdermal administration.
In many embodiments, the dosage form may be suitable for inhalation or nebulization.
In certain embodiments, the dosage form may be in the form of a sublingual, dermal or transdermal patch. The present invention has exemplified such patches using PVA plasticizing materials.
Suitable plasticizing materials may generally be characterized as non-toxic water-soluble materials for this particular application. Specific examples may include, but are not limited to, synthetic resins such as polyvinyl acetate (PVAc) and sucrose esters, and natural resins such as rosin esters (or ester gums), natural resins such as glycerol esters of partially hydrogenated rosin, glycerol esters of polymerized rosin, glycerol esters of partially dimerized rosin, glycerol esters of tall oil rosin, pentaerythritol esters of partially hydrogenated rosin, methyl esters of rosin, partially hydrogenated methyl esters of rosin, and pentaerythritol esters of rosin. In addition, synthetic resins such as terpene resins derived from alpha-pinene, beta-pinene and/or d-limonene, as well as natural terpene resins, may be used in the chewy matrix.
The invention can also be expressed by a pharmaceutical composition comprising a composition according to the above, and optionally further comprising a pharmaceutically acceptable carrier and/or excipient.
From yet another point of view, the present invention provides a kit comprising one or more dosage forms according to the above, and optionally further comprising a device for administration thereof.
In certain embodiments, the kits of the invention may comprise an inhaler or nebulizer. The present application relates in particular to compositions provided in the form of a mist in the context of various pulmonary conditions such as asthma.
From another point of view, the present invention provides compositions and dosage forms according to the above for improving the oral bioavailability of at least one lipophilic API comprised in the corresponding composition or dosage form.
From yet another point of view, the present invention provides compositions and dosage forms according to the above for improving the bioavailability of at least one lipophilic API contained in the corresponding composition or dosage form.
From yet another perspective, the present invention provides a series of methods for improving the oral bioavailability and/or bioavailability of at least one lipophilic API for treating a disorder or condition in a subject in need thereof, the main feature of such methods being the administration of a therapeutically effective amount of the compositions and dosage forms of the present invention to the subject.
It is another object of the present invention to provide methods for treating or alleviating a disorder or clinical or sub-clinical condition that can be remedied by treatment with one or more lipophilic APIs. The main feature of such methods is the administration of a therapeutically effective amount of the compositions and dosage forms of the present invention to a subject in need thereof.
More specifically, the present invention provides a method for treating or alleviating a disorder that can be remedied by treatment with a lipophilic API in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a solid water-dispersible composition of matter comprising at least one saccharide, at least one polysaccharide and at least one surfactant and at least one lipophilic API, and wherein the composition comprises more than one microparticles, each comprising more than one lipophilic nanosphere having an average size in the range of about 50nm to about 900nm, at least one lipophilic API being comprised in the microparticles and distributed inside and/or outside the lipophilic nanospheres in a predetermined ratio, thereby providing immediate and/or prolonged delivery of said lipophilic API.
In many embodiments, the administration of the lipophilic API may be oral, sublingual, buccal, rectal, topical, dermal, and transdermal.
In other embodiments, the administration of the lipophilic API may be by inhalation or nebulization.
In further embodiments, the administration of the lipophilic API may further comprise using a device that facilitates administration of the API.
In certain embodiments, the administration of the lipophilic API may be by sublingual, dermal or transdermal patches of the invention.
In certain embodiments, the methods of the invention may further comprise concomitantly administering to the subject at least one additional lipophilic or non-lipophilic API.
In many embodiments, additional lipophilic APIs may be provided in the compositions of the present invention.
These aspects may also be expressed in terms of the use of a composition as described above in the manufacture of a medicament for treating or alleviating a disorder or condition that may be remedied by treatment with a lipophilic API.
In many embodiments, the present invention provides the use of a composition as described above in the preparation of a medicament having one or more lipophilic APIs with improved bioavailability and/or improved bioavailability.
In yet another aspect, the present invention provides a method of preparing a composition having increased bioavailability and/or bioavailability of a lipophilic API by:
(i) Mixing an aqueous phase comprising at least one saccharide, at least one polysaccharide and at least one surfactant with an oil phase comprising at least one lipophilic API,
(ii) The mixture is emulsified to obtain a nanoemulsion,
(iii) The nanoemulsion is lyophilized or spray dried.
In another aspect, the present invention provides a method for increasing the loading of a lipophilic API contained in a composition by:
(i) Mixing an aqueous phase comprising at least one saccharide, at least one polysaccharide and at least one surfactant with an oil phase comprising at least one lipophilic API,
(ii) The mixture is emulsified to obtain a nanoemulsion,
(iii) The nanoemulsion is lyophilized or spray dried.
One particular application of the present technology is to provide a particularly attractive formulation of an API in a micronized sugar granule that can also be incorporated into a variety of foods, chocolate and candy.
In essence, the present invention provides a sugar particle comprising a porous sugar material and lipophilic nanospheres having an average size of between about 50nm and about 900nm such that the lipophilic nanospheres are contained in the porous sugar material, the sugar particle further comprising at least one edible sugar, at least one edible oil, at least one edible polysaccharide, at least one edible surfactant, and at least one API.
The term "porous sugar material" means a solid, sieve-like material that transports voids or pores that are not occupied by the primary structure of atoms of the solid material (e.g., sugar). The term herein encompasses materials having regularly or irregularly dispersed pores, as well as pores in the form of cavities, channels or interstices, having different pore size, arrangement and shape characteristics, as well as different porosities (ratio of pore volume to solid material volume) and compositions of solid materials of the overall material.
As has been noted, in many embodiments, the lipophilic nanospheres may have an average size in the range of about 50-900nm, and specifically in the range of about 50-100nm, 100-150nm, 150-200nm, 200-250nm, 250-300nm, 300-350nm, 350-400nm, 400-450nm, 450-500nm, 500-550nm, 550-600nm, 650-700nm, 700-750nm, 750-800nm, 800-850nm, 850-900nm, and 900-1000 nm.
In certain embodiments, the lipophilic nanospheres may have an average size in the range of about 100-200nm, and in particular in the range of about 100-110nm, 110-120nm, 120-130nm, 130-140nm, 140-150nm, 150-160nm, 160-170nm, 170-180nm, 180-190nm, and 190-200 nm.
In many embodiments, the size of the sugar particles can be in the range between about 10 μm and about 300 μm, and in particular in the range of about 10-50 μm, 50-100 μm, 100-150 μm, 150-200 μm, and 250-300 μm or larger in size.
In certain embodiments, the size of the sugar particles may be in the range between about 20 μm to about 50 μm, and in particular in the range of about 10-50 μm, 20-50 μm, 30-50 μm, and 40-50 μm, or up to at least about 20 μm, 30 μm, 40 μm, 50 μm.
Within the indicated size ranges, in many embodiments, the sugar particles of the present invention may have an irregular shape or form (embodiment 11).
In many embodiments, the edible sugar contained in the sugar particles may be obtained from plant or animal sources, synthetic sugars, or mixtures thereof.
In further embodiments, the edible sugar may be obtained from sugar beet, sugar cane, sugar palm, maple sap (maple sap), and/or sweet sorghum.
In certain embodiments, the edible sugar may be a monosaccharide and/or disaccharide selected from glucose, fructose, sucrose, lactose, maltose, galactose, trehalose, mannitol, lactitol, or mixtures thereof.
In many embodiments, the edible sugar may constitute between about 30% to about 80% (w/w) of the sugar particle, or more specifically about 20% -30%, 30% -40%, 40% -50%, 50% -60%, 60% -70%, 70% -80% and 80% -90% (w/w) of the sugar particle.
In many embodiments, the edible polysaccharide may be selected from maltodextrin and carboxymethylcellulose (CMC).
In many embodiments, the edible surfactant may be selected from the group consisting of ammonium glycyrrhizate, pluronic F-127, and pluronic F-68.
In many embodiments, the edible surfactant may be selected from one or more of monoglycerides, diglycerides, glycolipids, lecithins, fatty alcohols, fatty acids.
In certain embodiments, the edible surfactant may be a sucrose fatty acid ester (sugar ester).
In many embodiments, the edible oil may be obtained from a plant or animal source, a synthetic oil or fat, or a mixture thereof.
In certain embodiments, the edible oil may include cocoa butter (cocoa butter).
In many embodiments, the sugar particles of the present invention may further comprise one or more food colorants, taste or flavor enhancers, taste masking agents (taste masks), food preservatives.
A non-limiting list of materials suitable for this particular aspect is provided in appendix a.
Thus, in this particular aspect, the present invention may be considered a medical food (media food) comprising one or more lipophilic APIs dispersed in a food matrix. Such food substrates may be of the traditional food type (such as beverages, yogurt or candy) or nutritional liquids fed to the patient through a tube. Medical foods are typically administered under medical supervision to treat a particular disease.
The invention also provides compositions and methods for eradicating, preventing the development and destruction of microbial biofilms. The compositions of the invention may be applied to any tissue or organ of a subject's body by any of the methods disclosed herein to treat or prevent the evolution of such biofilms. The biofilm may alternatively be a biofilm formed on a surface of a device or tool (such as those used in medical facilities).
The term "about" in this text means a deviation of at most + -10% from the specified value and/or range, more particularly at most + -1%, + -2%, + -3%, + -4%, + -5%, from the specified value and/or range, at all occurrences thereof,
Deviations of + -6%, + -7%, + -8%, + -9% or + -10%.
Examples
Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. Some embodiments of the invention will now be described, by way of example, with reference to the accompanying drawings.
Example 1: physical Properties of the powder composition
1.1Maintenance of particle size in reconstituted compositions
By nanoemulsifying in liquid N 2 Is frozen and lyophilized (48 h) to prepare a powder composition comprising 30% alaska omega (omega 3). After nanoemulsification and lyophilization, the distribution and uniformity of particle size was evaluated using PDI (polydispersity index) measured by DLS (dynamic light scattering) after dispersing the powder to 1% (w/w) in TWD. Measurements were performed in triplicate. The PDI is related to granularity. PDI values indicate that the nanoemulsion and reconstituted powder contained a uniform and homogeneous population of particles with average sizes of 149nm±sd and 190nm±sd, respectively.
The results show that the particle size in the reconstituted powder composition is relatively constant and maintained relative to the source nanoemulsion, and in summary, this feature of each sample is uniform and homogeneous. The findings of particle size retention further indicate the same trend in saliva and GI.
1.2Maintenance of particle size after 1 month of storage
The powder was stored for 1 month and then reconstituted to 1% (w/w) or to 2% (w/w) in TWD and subjected to DLS or frozen TEM (transmission electron frozen microscopy) analysis. For DLS and frozen TEM, the average particle sizes in the reconstituted powders were 218nm±sd and 100nm±sd, respectively, indicating that the measurements are technology dependent.
In summary, the results demonstrate that the powder composition is relatively stable and retains the ability to reconstruct a relatively uniform population of particles in the nanometer range.
1.3Powder composition containing lycopene oil and industrial hemp oil
Using the above method, a powder composition was produced from lycopene oil and industrial hemp (1:1.4, respectively). DLS analysis was performed on the nanoemulsion and reconstituted powder (1% w/w). DLS analysis showed a single particle population in the nanoemulsion, with an average size of about 590nm, and two particle populations in the reconstituted powder, with an average size of about 272nm, and a small peak at 79 nm. The particle size did not increase after lyophilization.
The results indicated that the powder composition containing lycopene and technical hemp oil performed similarly to the powder containing omega 3 in terms of particle size retention and uniformity. In summary, the results indicate that the technique is applicable to a variety of types of lipophilic drug vehicles, i.e., oils, and combinations of oils.
1.4Preliminary stability study of cannabinoid-containing compositions
The powder compositions containing CBD or THC were stored at 45 ℃ (oven) for 1 day, 35 days, 54 days, 72 days and 82 days (3 months, corresponding to 24 months at RT). Particle size was assessed using DLS. The results are shown in table 1 and fig. 1.
TABLE 1 DS measurements in test samples
Temperature (temperature) AVG PDI Peak value
RT 150.5 0.208 163.2
At 45℃for 1 day 149.1 0.213 151.9
At 45℃for 35 days 160.2 0.25 159.6
At 45℃for 54 days 150.1 0.216 144.7
At 45℃for 72 days 150.1 0.212 143.3
At 45℃for 82 days 153.7 0.205 154
Average diameter of AVG (nm)
PDI polydispersity index
The results show that the particle size remains at 45 ℃ for at least three months, thus indicating that the powder composition has long-term stability and the ability to retain particle size when reconstituted in aqueous solution, and most likely also in GI.
1.5Composition containing lactose and industrial hemp oil
Nanoemulsions and corresponding powders containing lactose (as a sugar option) were prepared. A list of ingredients is detailed in table 2.
TABLE 2 specification of test samples
Lactose and lactose 80％ 90％ 100％ 110％ 120％
Ammonium glycyrrhizinate 3.05 3.05 3.05 3.05 3.05
Maltodextrin 13.68 13.68 13.68 13.68 13.68
Lactose and lactose 16 18 20 22 24
Water and its preparation method 145.74 145.74 145.74 145.74 145.74
Industrial hemp oil 15.74 15.74 15.74 15.74 15.74
Nanoemulsions were prepared from lactose solution (80%) and maltodextrin (25-50 ℃). Lactose was added to the mixture to a concentration of 90%, 100%, 110%, 120% (relative to the initial concentration) along with ammonium glycinate and technical hemp oil. The nanoemulsion was homogenized by M-110EH-30 at 10,000-20,000PSI (25-50 ℃) for x 4 cycles. The following method was used to prepare powders: (1) lyophilization: freezing (-25 ℃ to-86 ℃) and lyophilization (12-24 h, -51 ℃,7.7 mbar); or (2) spray drying: peristaltic pump (flow rate of 8.5-20g/min, air temperature of 110-150deg.C, air flow of 0.4-0.5 m) 3 /min, nebulizer pressure 0.15 MPa). DLS analysis of the reconstituted powder is shown in table 3.
TABLE 3 DS measurements in the samples tested
Lactose concentration Drying technology Yield (%) T air discharge Pump flow (g/min) Average size (nm)
80％ Spray dryer 54.8 62 8.78 135.3
90％ Spray dryer 63.8 62 9.66 127.6
100％ Spray dryer 87.5 63 10.4 125.6
120％ Spray dryer 87 63 10.1 124.6
80％ Freeze dryer 100％ NR NR 136.1
100％ Freeze dryer 100％ NR NR 127.8
110％ Freeze dryer 100％ NR NR 125.4
120％ Freeze dryer 100％ NR NR 124.5
The results indicate that the particle size is maintained under various procedures and lactose concentrations. In summary, the results indicate that lactose can be used as an alternative sugar without compromising the core properties of the composition.
1.6Loading capacity and distribution of lipophilic components
Nanoemulsions were prepared with the following various types of oil vehicles: omega 7, TG400300, EE400300. The surface oil content was determined by hexane. The powder (5 g) was washed with hexane (50 ml), filtered, and washed with hexane (5 ml) (. Times.4). At N 2 The filtrate was then subjected to Loss On Drying (LOD) until the weight was stable. The oil content inside the nanospheres was estimated as:
ω7-52.67％
TG400300-30.67％
EE400300-35.33％
the results indicate that up to about 50% of the lipophilic vehicle can be incorporated into the lipophilic nanospheres, depending on the type of oil. For lipophilic APIs dissolved in this and other types of vehicles, a similar distribution can be assumed.
The results indicate that a substantial proportion of the lipophilic carrier (and lipophilic API) can be present outside the nanospheres. This finding strongly supports the concept of differential bioavailability and two-stage release of lipophilic APIs characteristic of the compositions of the present invention.
More recent studies have shown that more than 80% and 90% of lipophilic carriers and lipophilic APIs can be incorporated into nanospheres.
Taken together, these results indicate the high loading capacity of the lipophilic carrier and lipophilic API in the powder compositions of the present invention.
1.7Encapsulation capacity of the composition
The encapsulation capacity is estimated by the difference between the initial amount of API and the final amount of the composition that is not embedded in the composition. Four different types of powders were prepared using the above method with the following lipophilic carriers/APIs:
vitamin D3 oil
Passion fruit oil (Passionfruit oil)
Medium Chain Triglyceride (MCT) oils
Pomegranate seed oil
Unencapsulated lipophilic vehicle/API was removed with hexane (1 g of powder was shaken in 10ml of n-hexane for 2 min), the product was filtered and washed with hexane (×3), and the content of entrapped lipophilic vehicle/API was measured using solvent extraction-gravimetric method. The results are shown in table 4.
TABLE 4 embedded oil content in the compositions tested
Oil/active substance Before washing (g/100 g) After washing (g/100 g) Encapsulation efficiency
Vitamin D 30.57 30.50 99.8％
Passion fruit 30.31 29.46 97.2％
MCT 29.06 28.79 99.1％
Pomegranate 29.16 26.11 99.8％
The results indicate that the loading capacity of the lipophilic vehicle/API into the composition of the present invention is quite high, to the extent of about 97.0% -99.8%.
1.8Maintenance of particle size in hypertonic solutions
The feature of maintaining particle size was further studied in saline solutions that mimic the amount of penetration on skin. For compatibility with the skin, surface preparations are expected to be stable and retain their characteristic properties under conditions of high salinity (typically 0.5% -0.8% nacl).
The nanopowder was resuspended (1% w/w) in saline solution (0.75% NaCl) and TDW. DLS analysis was performed as above. The tests were performed in triplicate. Raw data of the distribution of particle size is given below:
water:z Avg;164.1nm, pdi:0.232, peak 1:175.3 (99.3%), peak 2:3508 (0.7%).
Brine solution: z AVG;158.2nm, pdi:0.236, peak 1:154.3 (98.6%), peak 2:4085 (1.4%).
The results show a small difference in particle size between the saline solution and water, 158nm versus 164nm, respectively. The results indicate that the powder compositions retain their particle size and uniformity in the hypertonic solution.
Maintaining nano-size and larger surface area may provide deeper penetration of the API into the skin and improved efficacy. In summary, the present study shows that the powder composition of the invention has the potential to provide improved preparation for surface delivery of therapeutically active substances.
1.9Compositions containing additional lipophilic vehicles
Powders were prepared using the above method with different lipophilic carriers:
sample 1-fish oil FO 1812ultra,50% oil
Sample 2-KD-PUR 490330TG90 Ultra,30% oil
Sample 3-KD-PUR 490330TG90 Ultra,50% oil
Particle size was evaluated in nanoemulsions and reconstituted powders. In the corresponding nanoemulsions and reconstituted powders, the particle size surprisingly remains stable, with average dimensions in the range of about 140-160 nm.
In summary, the different compositions show uniformity of particle size in the transition from nanoemulsion to solid form. The particle size remains stable during the drying process, which is very surprising in view of the elevated temperature and drying conditions. This experiment shows that this technology has high applicability to many types of lipophilic vehicles and APIs.
Example 2: surprisingly chemical stability of the active substances
2.1Stability of compositions containing cannabis extracts
Cannabinoids are particularly susceptible to chemical and photolytic degradation. Nanoemulsions were prepared with a full spectrum of hemp oil (50%) obtained from two cannabis strains (THC or CBD rich) and other core components of the compositions of the present invention.
The reconstituted powder produced a characteristic particle size of about 150nm and produced the expected cannabinoid spectrum in the oil. The powder was stored in an aluminum bag in a 40 ℃ chamber under the following conditions:
1g per bag
O 2 Scavenger agent
Silica desiccant
The experiments were performed on powders rich in THC and CBD extracts (powder a and powder B) in two independent runs. Cannabinoid analysis was performed using HPLC at baseline (0), 30 days, 45 days and 83 days (associated with 10 months, 13 months, 24 months of RT). The results are shown in tables 5 and 6.
TABLE 5 analysis of cannabinoids in powder A
Figure BDA0004113560050000331
TABLE 6 analysis of cannabinoids in powder B
Figure BDA0004113560050000332
The results indicate that the compositions of the present invention provide long term stability of the API (cannabinoid, and cannabinoid complex composition (complex compositions of cannabinoids)) for at least 24 months at RT. The recommended storage conditions should also include having O 2 Aluminum bags of scavenger and/or moisture desiccant.
In summary, under these conditions, the maximum degradation rate is not more than 2.5% of the total cannabinoid content, and the maximum degradation rate of specific cannabinoids (THC and CBD versus CBN and CBG) is even lower. This finding is also consistent with the content of CBN (e.g. in powder a) as a known marker of cannabinoid degradation.
2.2Stability of compositions comprising lycopene
Carotenoids are sensitive to elevated temperatures, pro-oxidative substances and acidic pH. Nanoemulsions were prepared with lycopene oleoresin (lycopene oleoresin) (6% lycopene w/w) and other core components of the present composition. The powder (4 g) was vacuum heat sealed in an aluminum bag with moisture and oxygen scavengers and stored at RT (25 ℃), 4 ℃ and 40 ℃ for 0, 30 and 90 days (in duplicate). The test products were analyzed by visual appearance, DLS and HPLC at the indicated time points.
Visual analysis indicated that all samples maintained a typical consistent texture and color during the storage phase. DLS analysis indicated that the feature particle size of 225-272nm was relatively maintained. The results are shown in table 7. HPLC analysis showed minimal loss of lycopene during the storage phase, i.e. 7%, 3% and 1% for samples stored at RT, 4 ℃ and 40 ℃, respectively.
TABLE 7 DLS analysis of lycopene containing compositions
Figure BDA0004113560050000341
In summary, the results demonstrate that the present compositions provide an API such as lycopene with an extended shelf life and prevent oxidation and degradation thereof. Prolonged stability at 40 ℃ for 90 days corresponds to RT 2 years. The recommended conditions should also include an aluminum pouch with a moisture scavenger and an oxygen scavenger.
2.3Stability of vitamin D3-containing compositions
The vitamin D3 containing powder was stored at 40 ℃/RH 75% for 90 days. Vitamin D3 and ethoxylated vitamin D3 degradation products were detected by HPLC. Analytical testing was further validated by an externally authorized laboratory (Eurofins). The results are shown in table 8.
TABLE 8 HPLC analysis of vitamin D3-containing compositions
Figure BDA0004113560050000351
The cholecalciferol test is consistent with certificate (1M iu/g). The results indicate that the encapsulated fraction contains 28% -29% vitamin D3 compared to 30% vitamin D3 in the original oil product, indicating minimal loss of active during the production process. Furthermore, only minimal degradation (up to 5% API) was observed during the storage phase. The difference between the replicates can be explained by ligation (solding). The powder has much fewer degradation products than the oil form. This study shows the potential stability of the powder form at RT for a period of 2 years.
The above studies show that the powder composition of the present invention has a surprisingly long shelf life and the ability to maintain the chemical stability of the API. This feature is very surprising, especially given that the production process involves a high pressure, aqueous environment, both of which are detrimental to the lipophilic molecules, and also given that the reduction in particle size and the increase in surface area are expected to increase the oxidation and chemical instability of the active substance. These findings further support the pharmacological applicability of the compositions and methods of the present invention.
2.4Stability of fish oil-containing compositions
Studies using compositions containing fish oil further supported the protective properties of the powder compositions of the invention. Fish oil (60% omega 3 fatty acids w/w) is known to oxidize easily by the formation of primary and secondary oxidation products.
Powder compositions were prepared from 40% fish oil (w/w) and other core components. The oil and powder samples were exposed to ambient oxygen, vacuum heat sealed, and stored at 4 ℃ for 28 days. The primary oxidation products (peroxides; PV) and the secondary oxidation products (anisole; AV) were measured on days 0, 14 and 28. TOTOX value (total oxidation state) is calculated using the following formula:
TOTOX＝AV+2*PV。
the results are shown in fig. 2. The results show that from day 0 up to day 14, the powder composition has significantly lower TOTOX, i.e., significantly lower primary and secondary oxidation product concentrations, compared to the oil form. The results on day 0 also show that the powder production process does not lead to degradation despite exposure to water and oxygen.
In summary, the results support the surprising ability of the powder composition to protect the active and to prevent oxidation/degradation thereof, most likely due to encapsulation. This property is also consistent with the long-term stability characteristic of the compositions of the present invention previously shown.
Example 3: surprisingly load capacity
The loading capacity of the powder composition was further investigated in compositions comprising concentrated hemp oil. The nanoemulsion was produced by the above method with a raw RSO high THC concentrate (raw RSO high THC concentrate) (1 g). The nanoemulsion and reconstituted powder produced particles having a characteristic size of about 150 nm. The reconstituted powder was subjected to cannabinoid analysis using HPLC. Table 9 shows the calculated cannabinoid content compared to the actual cannabinoid content.
TABLE 9 THC content measured and THC content calculated
w/w％ Calculated as Measured by
Δ9-THC 8.945％ 8.45％
CBG 0.276％ 0.24％
For Δ9-THC and CBG, the ratio between calculated and actual content was 94.91% and 86.9%, respectively, indicating minimal loss of active. The ratio of oil carrier relative to total powder material further suggests the surprisingly high loading capacity of lipophilic carrier and API.
Example 4: incretin surprisingly oral bioavailability
4.1Pharmacokinetic profile in plasma
The pharmacokinetic Profile (PK) of the compositions of the invention was evaluated in a rat model. Two types of CBD/THC compositions were compared in the study: the powder compositions (LL-P) and similar oil forms (LL-oil) of the present invention release API in plasma. The following endpoints were used for the study:
i. mortality and morbidity monitoring—daily.
Body weight monitoring-during adaptation and prior to dosing.
Clinical observations-pre-oral administration and 2 hours after oral administration.
Blood drawing-at time points of 15min, 30min, 45min, 60min, 90min, 120min, 240min, 420min and 24 h.
v. terminate and organ collect (brain, liver) at 45min, 60min, 90min, 120min, 240 min.
Study classical Pharmacokinetic (PK) analysis was used in animals (n=18) divided into 6 groups (3 animals per group).
Materials and methods
Test item I: CBD/THC powder (LL-P): LL-CBD-THC 30% oil in powder.
Test item II: CBD/THC oil (LL-oil): LL-CBD-THC oil diluted in technical hemp oil.
Oral doses were prepared as follows: 150mg of LL-P was dissolved in 2.85mg of TDW; 45mg of LL-oil was diluted in 1ml of technical hemp oil (per animal).
Male rats/18/376/456 g (sex/number/body weight) were grouped (average body weight deviation of + -20% per group) and acclimatized (8 days). The study (1 cycle) was performed in 6 groups (x 3 animals, and x3 time points). Blood samples were collected and stored at indicated time points. The group assignments are shown in table 10. Animals were observed daily for toxic/adverse symptoms before and after administration. No conditions, pain or distress were found during the whole study period.
TABLE 10 group allocation
Figure BDA0004113560050000371
Figure BDA0004113560050000381
Results
PK profiles of active substances released from LL-P and LL-oil (CBD and THC) in plasma are shown in tables 11-12 (time periods 0-24h and 0-7 h) and fig. 3A and 3B.
TABLE 11.0-24 h PK analysis
Figure BDA0004113560050000382
TABLE 12.0-7 h PK analysis
Figure BDA0004113560050000383
Conclusion(s)
LL-P shows a significantly faster release profile in plasma compared to LL-oil, for both CBD (Tmax 0.75h compared to 4 h) and THC (Tmax 0.75h compared to 2h; LL-P and LL-oil respectively). The observed Cmax of plasma CBD was more than doubled (82.5 ng/mL compared to 35.8ng/mL, LL-P and LL-oil respectively). Plasma THC Cmax was also significantly higher (242.7 ng/mL compared to 103.4ng/mL, LL-P and LL-oil respectively). The calculated AUC (area under the curve) reflects an oral bioavailability of approximately 40% higher CBD in LL-oil than in LL-P, but similar for both forms of THC.
4.2Biodistribution in tissues
Similar studies compared the API release of CBD/THC compositions in powder (LL-P) and oil (LL-oil) forms in plasma and selected organs (liver and brain). The study used the above endpoints except:
blood drawing-at time points of 0min, 15min, 30min, 45min, 60min, 90min, 120min and 240 min.
Study classical PK analysis was used in animals divided into 2 groups (n=12).
Materials and methods
Test item I: CBD/THC powder (LL-P): LL-CBD-THC 30% oil in powder
Test item II: CBD/THC oil (LL-oil): LL-CBD-THC oil diluted in technical hemp oil
Oral doses were prepared as follows: 225mg of LL-P was dissolved in 4.275mg of TDW; 67.5mg of LL-oil was diluted in 1ml of technical hemp oil (per animal).
Male rats/12/376/456 g (sex/number/body weight) were grouped (average body weight deviation of + -20% per group) and acclimatized (8 days). The study (1 cycle) was performed in 2 groups (x 6 animals, x 3-4 time points). Blood samples were collected and stored at indicated time points. Organs (brain, liver) were collected and stored after terminal blood sampling and perfusion. The change in organ weight was not significant. The group assignments are shown in table 13. No conditions, pain or distress were found during the whole study period.
TABLE 13 group allocation
Figure BDA0004113560050000391
Figure BDA0004113560050000401
Results
PK analysis of active substances released from LL-P and LL-oil (CBD and THC) in plasma, brain and liver are shown in table 14, and fig. 4A-4B (plasma) and fig. 5A-5D (liver and brain).
TABLE 14 PK analysis of CBD and THC in plasma, brain and liver
Figure BDA0004113560050000402
Figure BDA0004113560050000411
Conclusion(s)
In plasma, LL-P shows a two-phase release profile, with an immediate increase in API during the first hour, followed by a decrease, and continuing another increase until the end of the study phase. In contrast, LL-oil shows a single-stage release profile of active substances during the study phase (240 min).
PK profile in liver and brain is similar to plasma profile. LL-P shows significantly faster penetration of both APIs into the organization compared to LL-oil. In the brain, the Cmax of CBD was higher in LL-P than in LL-oil (122.6 ng/g vs. 95.6ng/g, respectively), as was the Cmax of THC (206.9 ng/g vs. 115ng/g, respectively). Similar results were observed in the liver.
These results demonstrate that the oral bioavailability of the LL-P composition in plasma and tissue is superior to LL-oil. In addition, LL-P compositions can have a composition that provides combined immediate release and prolonged active releaseTwo-phase release profile Is provided.
Example 5: bioavailability of vitamin D3-containing compositions
The favourable oral bioavailability of the compositions of the invention is further supported in studies comparing PK plasma profiles of vitamin D3 containing compositions in powder and oil form. Nanoemulsions were prepared according to standard protocols using both lyophilization and spray drying. Table 15 shows that the powder compositions maintained particle size, dissolution time and other characteristic features.
TABLE 15 QC test D3 for powder compositions containing vitamin D3
Figure BDA0004113560050000412
Figure BDA0004113560050000421
PK analysis was performed in rat plasma (n=9) after administration of a single oral dose of cholecalciferol (1 mg/kg body weight). Blood samples were collected at 0h, 0.25h, 0.5h, 1h, 1.5h, 2h, 4h, 8h, 24h, 32h, 48h, 56h, 72h, 80h, 96h, and 104h (4 days). The steady state cholecalciferol concentration in plasma was measured by gas-liquid chromatography. Parameters were compared after subtracting the baseline concentration and the baseline concentration was used as a covariate. The results are shown in fig. 6.
The results indicated that vitamin D3 in the powder composition peaked rapidly, reaching a concentration in plasma of twice that relative to the oil form, and remained further for at least 60h (3 days) at lower steady state concentrations. As reflected in AUC (area under the curve), the bioavailability of vitamin D3 in powder form was 20% higher than vitamin D3 in oil form, and the half-life was 15% longer than vitamin D3 in oil form (p < 0.05).
In summary, the results demonstrate improved oral bioavailability of lipophilic APIs in the powder compositions of the present invention.
Example 6: enhanced biological accessibility of active substances
6.1In vitro study to simulate conditions in GI
The study explored the behavior of the two active substances thymol (2-isopropyl-5-methylphenol) and carvacrol (2-methyl 5- (1-methylethyl) phenol) found in oregano oil. Oregano oil is known for its beneficial properties, including antioxidant, free radical scavenging, anti-inflammatory, analgesic, antispasmodic, antibacterial, antifungal, preservative and antitumor activity. Both compounds have low solubility and permeability due to their lipophilic nature and susceptibility to degradation under acidic conditions in the stomach.
The in vitro semi-dynamic digestion model was used to evaluate the bioavailability of thymol and carvacrol in the form of raw oil compared to the powder of the composition of the invention. The bioavailability reflects the extent of GI digestion, i.e., the amount of compound released in the GI tract and made available for absorption (e.g., into the blood stream). This parameter also depends on the digestive transformation of the compound and its corresponding uptake into the intestinal cells, as well as the pre-systemic metabolism, intestinal metabolism and hepatic metabolism. In vitro biological accessibility can be assessed according to the following equation:
Bioavailability (%) = (thymol and carvacrol content after in vitro digestion/initial thymol and carvacrol content) x 100
There are several types of in vitro digestion models: static models, semi-dynamic models, and dynamic models. The static model is characterized by the initial conditions (pH, enzyme, concentration of bile salts, etc.) of the individual groups of each part of the GI tract. It is relatively simple and has many advantages, but generally does not provide a realistic simulation of complex in vivo procedures. In contrast, dynamic digestion models also include corrections for geometry, biochemistry, and physical forces to better reflect in vivo digestion (e.g., continuous flow of digestive contents from stomach to intestine, addition of HCl, flow of pepsin, gastric emptying, and controlled bile secretion). A semi-dynamic model is an intermediate model that combines the advantages of both methods. It comprises passing HCl in the stomach phase and NH in the intestine phase 4 HCO 3 But without continuous flow of digestive contents, and the intestinal phase begins after the gastric phase (unlike in the dynamic model).
Materials and methods
The API is tested in the following form: (1) oregano oil: 365 μl (-300 mg oregano oil) comprising thymol 1.26mg and carvacrol 26.31 mg; and (2) oregano powder: 1.11g of the powder composition of the invention comprising 1.30mg thymol and 26.31mg carvacrol. A powder composition was produced according to the above method, yielding a 30% load of oregano oil (w/w).
In the semi-dynamic digestive system, both formats were tested using the info get protocol. The concentrations of thymol and carvacrol were measured at baseline and after 2h (representing the end of the stomach). Samples were analyzed by gas chromatography-mass spectrometry (GC-MS) using a fused silica capillary column (30 m,0.25 mm), a source temperature of 230 ℃, a tetrode temperature of 150 ℃ and a column oven temperature of 250 ℃ for 3 min. A sample of digests (1 μl) was injected and the concentration of analyte (peak area relative to standard peak area) was calculated. The calibration curve shows the linearity of the MS response. All preparations were analyzed by GC-MS before and after in vitro gastric digestion at the relevant time points. Chemical analyses of the oil and powder compositions were performed to evaluate the loss of active substance during powder preparation.
Results
During the powder preparation process, the concentrations of thymol and carvacrol were reduced by 7% and 10%, respectively. In vitro digestion studies of both forms showed that at the end of the gastric phase (2 h post intake), the bioavailabilty of carvacrol was 19% and 41% (more than twice) for the oil and powder forms, respectively. Similarly, for oil and powder forms, the bioavailability of thymol is 16% and 37%. For the oil and powder forms, the bioavailability of the two APIs was 19% and 41%, respectively. In other words, while only about 20% of the active in the oil composition survived the acidic pH in the stomach, the API survival in the powder composition increased significantly. The results are shown in fig. 7.
Conclusion(s)
In summary, the results show that the powder compositions of the present invention can protect the active substances from gastric degradation and thereby improve their oral bioavailability and bioavailability to circulation and tissues.
6.2Comparative study of powders included in enteric capsules
Similar studies were performed including the oil form and the powder form as above and the powder form in enteric capsules (acid-resistant coating). Thymol and carvacrol concentrations were measured at baseline and after 2h (end of gastric stage), with the calculation of bioavailabilities as above. In addition, the powder in the enteric capsule was transferred from the stomach stage to the duodenum stage and tested after 4h (end of duodenum stage).
Results
For the oil and powder forms and the powder in the enteric capsule, the bioavailabilities of thymol and carvacrol at the end of the gastric phase were 19%, 41% and 89%, respectively, indicating significant differences between the different types of compositions. Similar results were obtained for the active alone. Taking thymol as an example, the bioavailability is 16%, 37% and 87%, respectively. The results are shown in fig. 8A-8C. At the end of the duodenal phase, the bioavailability of the powder in the enteric capsule was 79% (for both actives). The results are shown in fig. 8D. The bioavailability of carvacrol was 78% and thymol was 97%.
Conclusion(s)
The results indicate that the protective effect of the powder compositions can also be enhanced by the addition of a functional coating, thereby even further improving their gastric and duodenal bioavailability.
In summary, the present invention provides a highly relevant pharmaceutical platform for formulating poorly water soluble APIs to achieve improved oral bioavailability and bioavailability of incorporated active substances.
Example 7: composition for incorporation into PVA film
7.1Compositions for incorporation into sublingual patches
Experiments explored the use of PVA sublingual membrane technology. Powders containing 30% -50% oil were reconstituted to 5% (w/w) in TDW. PVA solution (4.5%) was prepared from PVA powder (86-89 hydrolyzed PVA) in TDW. The PVA solution was mixed with the nanoemulsion in a ratio of 4% and 0.5%, respectively. Samples (3 g, x 6 samples) were cast into aluminum molds and dried at 38 ℃ for 24 hours. Some samples included flavoring. The sample specifications are detailed in table 16.
TABLE 16 specification of samples
Figure BDA0004113560050000451
All samples produced films, the differences in shape being attributable to the different wetting properties. Table 17 shows a comparison between the actual dry weight and the theoretical weight, indicating complete evaporation of water during drying. The nanoemulsion is uniformly dispersed across the membrane.
TABLE 17 estimation of actual weight and theoretical weight
Figure BDA0004113560050000452
Selected samples (n=3) were dissolved in 50ml TDW for 20-40min at 37 ℃. Analysis of the oil content of sample 6 (0.15 g dry weight) produced about 0.017g oil-83.6% of the theoretical content. The resulting film (1 x 1cm 2 100 μm thick) was placed under the tongue and the time to complete dissolution was measured.
The results show that the powder of the invention is suitable for formulation into polymer films. The solid particles are uniformly immobilized in the polymerized film to produce solid-in-solid dispersion (solid-in dispersion). Upon dissolution, the particles are completely released from the PVA matrix. In summary, sublingual membranes provide an attractive approach for oral and transmucosal delivery of certain types of lipophilic APIs.
7.2Compositions for incorporation into skin and transdermal patches
Powders containing 30% -50% oil were reconstituted to 0.5% (w/w) in TDW. PVA solution (8%) and PVA/nanoemulsion mixture were prepared as above, cast into aluminum molds and dried. The specifications of the samples were similar (see table 16). The resulting film (2 x 1cm 2 100 μm thick) was dissolved in TDW at 37 ℃ and analyzed for oil content. The estimates of particle size before and after release from the film are shown in table 18.
TABLE 18 estimation of particle size
Figure BDA0004113560050000461
The nanoparticle size has a significant impact on the surface area of the API and its rate of penetration through the biofilm. In view of this, the discovery that particle size is maintained in PVA formulations is particularly important; this is true whether or not exposed to polar environments (PVA film), temperature and drying. After drying, the solid particles are uniformly immobilized in the polymeric film, thereby producing a solid-in-solid dispersion. The stability of this structure can be attributed to the unique nanoparticle properties of the compositions of the present invention. After dissolution, the particles are completely released from the polymer.
In summary, the results demonstrate that the powder compositions of the present invention can be incorporated into pharmaceutical dosage forms, such as dermal films, thereby providing an attractive innovative approach to the dermal and transdermal delivery of active substances. The natural humidity of the skin causes the membrane to slowly dissolve, thereby slowly releasing the nanoparticle lipophilic active substance embedded in the membrane until the membrane is completely dissolved and the active substance penetrates into the circulation through the epidermis layer. All of these make skin (dermal) patches a particularly advantageous dosage form for prolonged delivery of active substances through the skin (skin).
Example 8: enhanced penetration through the skin
The penetration through the skin was studied by comparing the corresponding powder and oil forms in an ex vivo human skin model with a composition comprising vitamin a and CBD. The results are shown in fig. 9 and 10A-10C.
The results show that the powder composition of the invention has significantly enhanced penetration through layers of human skin compared to the corresponding oil form. For example, for vitamin a, the powder composition has a 6-fold higher permeability through the full thickness of human skin than the corresponding oil form (fig. 9). For CBD, the powder form is more permeable through the stratum corneum layer 1 outermost layer, and the permeability through stratum corneum layer 2 is about 4 times higher (fig. 10A), yielding an API synergy of about 10 times higher in the whole epidermis (fig. 10B) and a significantly higher rate of cumulative transport of the API into deeper layers of the skin (fig. 10C).
Example 9: composition in the form of a mist (nebulizer)
An attractive method of administration, especially for certain types of APIs, is by inhalation devices or nebulizers. To this end, the powder composition was loaded into a household atomizer and the product was analyzed for particle size and other characteristic properties. A powder (an example of a lipophilic API) containing 30% -50% oil was dissolved in TDW to a concentration of 20% to produce a nanoemulsion, which was diluted to 10%, 4%, 2% and 1%. The sample specifications are detailed in table 19.
TABLE 19 measurement of particle size
Figure BDA0004113560050000471
Figure BDA0004113560050000481
A sample of nanoemulsion (2 ml) and a water control were loaded into the device. Nanoemulsion a was run twice for comparison. Upon activation of the device, the fog is clearly visible for the recorded time. Residual nanoemulsion on the walls of the device was visible. Before and after each test, the suction cup was weighed on a laboratory scale (precision 0.01 g) and the residual weight was calculated.
The residual amounts ranged from 0.39g to 0.71g (17.7% -32.2%), with an average of 0.54g. (about 25.4%). The nanoemulsion s.g ranged from 1.01 to 1.08g/ml, with the average residual amount being similar to distilled water, depending on the nanoemulsion concentration.
In summary, the results indicate that the reconstituted powder composition can be used in a nebulizer to produce a mist form particulate nanomaterial that can be inhaled into the respiratory tract. The effectiveness of mist generation from nanoemulsions is equivalent to water.
Example 10: antibiotic-containing composition
This study investigated the potential of clarithromycin, an antibiotic against Pseudomonas aeruginosa (Pseudomonas aeruginosa), to be encapsulated in the compositions of the present invention. Pseudomonas aeruginosa (P.aeromonas) is the primary pathogen in the lungs of patients with cystic fibrosis. Such bacterial strains are known for their ability to form biofilms on biological and non-biological surfaces, which makes them particularly resistant to host immune defenses and current antibiotic therapies. Clarithromycin, a novel semisynthetic macrolide, is a lipophilic molecule that exhibits broad spectrum antimicrobial activity against both gram-positive and gram-negative aerobic bacteria.
The clarithromycin-containing composition was prepared by a cold physical process. The powdered clarithromycin composition is dissolved in water to obtain a nanoemulsion. Control free clarithromycin was dissolved in 1% DMSO. The emulsion was dried using lyophilization. Samples were tested in three independent experiments, each in triplicate. Particle size was measured using DLS. MIC data (minimum inhibitory concentration) of formulated and free antibiotics were compared.
The results show that the powder composition containing the antibiotic retains its characteristic physical properties, including a nano-particle size of about 180nm (average diameter). The specification and MIC data for the nanoemulsions are summarized in tables 20 and 21.
TABLE 20 measurement of particle size
Clarithromycin powder composition Finely grinding white powder
Particle size (nanoemulsion) 150-200nm
Excipient Disaccharides, polysaccharides and natural emulsifiers
PH (nanometer emulsion) 4.4
Dissolution time <90
Moisture content <2
TABLE 21 MIC in powder composition and oil composition
Powder composition containing clarithromycin Free clarithromycin
0.03125％ 0.0625％
The results show that: pseudomonas aeruginosa (highly resistant strain) is more sensitive to the powder composition containing antibiotics than to the free form, the MIC of the powder composition was 0.03125% mg/L compared to 0.0625% in the free form (P < 0.001). In other words, the results indicate that a powder composition with clarithromycin achieves a significant inhibition (50%) of pseudomonas aeruginosa growth and amplification with a lower effective dose of clarithromycin than the free form of the same antibiotic.
In summary, the results show a significantly increased susceptibility of pseudomonas aeruginosa to clarithromycin containing powder compositions (50%, P < 0.05), demonstrating the applicability of the present technology to enhance the efficacy of known lipophilic antibiotics against pathogenic bacteria, including highly resistant strains.
The results further demonstrate that the powder composition may have the ability to disrupt and/or enhance the permeation of the active substance through the bacterial biofilm. The powder composition is a substantially dispersed emulsion coated negatively charged lipid droplet. The increased potency of the drug found at present can be explained by (1) the benefits of small particle size providing penetration of the drug and its accumulation in the bacterial biofilm; (2) Negatively charged nanoparticles are generally known to penetrate more easily into biological membranes; (3) The diffusion coefficient depends on the interaction of the drug with the EPS bacterial matrix that builds the biofilm.
In other words, the powdered clarithromycin composition has the potential to enhance the absorption and accumulation of antibiotic active substances in microbial biofilms, likely due to the improved solubility of the emulsified lipid particles. Thus, the present technology provides a new platform for the development of new antimicrobial agents and delivery systems for the formulation of lipophilic antibiotics and targeting microbial biofilms.
Example 11: formulation in micronized sugar particles
11.1Micronized sugar particles
Using the present technology, example formulations of micronized sugar were prepared from sucrose, maltodextrin, sugar esters (SP 30) and cocoa butter. The amounts and proportions of the ingredients are detailed in table 22. An example scheme of the production process will be described in further detail below.
TABLE 22 amounts and concentrations of ingredients
Composition of the components Total amount (g) Concentration in Dry formulation (% w/w)
Sucrose 610 61
Maltodextrin 150 15
Sugar ester (SP 30) 40 4
Cocoa butter 200 20
Added water (DDW) 2200 NR
* Total dry weight of all ingredients: 1000g
The preparation process comprises the following basic steps:
i. sucrose and maltodextrin were mixed with DDW.
Sugar ester (Sp 30) was added and the solution was heated to 50deg.C to dissolve the ingredients completely.
Adding cocoa butter and homogenizing the solution to produce a homogeneous emulsion.
Feeding the emulsion to a high pressure microfluidizer (4 bar, 16,000PSI x3 cycle) producing nanodroplets ranging in size from about 100nm to 200 nm.
The nanoemulsion was frozen (-30 ℃) and lyophilized until completely dried (about 2 days at 0.04 mbar). Optionally, the frozen nanoemulsion is spray dried at about 190 ℃.
The powder product was analyzed by Scanning Electron Microscopy (SEM). The product images in FIGS. 11A-1B show smooth finely granulated sugar particles in the size range of 20-50 μm. In summary, the results show that the sugar powder of the present invention is relatively uniform in texture and size, with smooth and finely granulated particles of less than 50 μm.
11.2Entrapment of nanodroplets in sugar particles
Sugar particles containing vitamin E oil (examples of lipophilic APIs) were analyzed using a frozen transmission electron microscope (frozen TEM). The samples were prepared in a Controlled Environment Vitrification System (CEVS) with humidity at saturation to prevent evaporation of volatiles and a temperature of 25 ℃. The solution (1 drop) was placed on a carbon coated perforated polymer film supported on a 200 mesh TEM grid. By removing the excess solution, the droplets are converted into thin films (< 300 nm). The grid was cooled in liquid ethane at-183 ℃. Frozen TEM imaging was performed at 200kV on Thermo-Fisher Talos F200C. The micrograph is recorded with a Thermo-Fisher Falcon camera (4 k x 4k resolution). The samples were examined in TEM nanoprobe mode using a voltage phase plate. Imaging was performed in low dose mode and acquired with TEM TIA software.
The frozen TEM section images in fig. 10A-10D show a population of smooth surface spherical nanodroplets with average sizes in the range of about 80-150nm, embedded in the sugar particles.
Appendix A
A1. Therapeutic agent classes associated with the compositions of the present invention
Analgesics include non-narcotic and narcotic analgesics
Antacid preparation
Anxiolytic drug
Antiarrhythmic agents
Antibacterial agent
Antibiotics include naturally occurring, synthetic, broad spectrum antibiotics
Anticoagulants and thrombolytics for arterial or venous thrombosis
Anticonvulsant drug
Antidepressants include mood-enhancing antidepressants: tricyclic, monoamine oxidase inhibitors and SSRI
Antidiarrheal agents include antidiarrheal products and agents for slowing down intestinal muscle contraction
Antiemetic medicine
Antifungal agents include agents affecting hair, skin, nails, and mucous membranes
Antihistaminic agents
Antihypertensives include diuretics, beta-blockers, calcium channel blockers, ACE (angiotensin converting enzyme) inhibitors
Anti-inflammatory agent
Antitumor drug (antineoplastics)
Antipsychotics are also powerful sedatives (major tranquilizer)
Antipyretic medicine
Antiviral agents include treatment and temporary protection against viral infections
Barbiturates (see hypnotics).
Beta-blockers
Bronchodilators
Cold drugs are associated with dull pain (ache), pain (pain) and fever associated with the cold
Corticosteroids in the context of immunosuppression, malignancy or deficiency
Cough medications include narcotic and non-narcotic inhibitors
Cytotoxins as antitumor and immunosuppressant agents
Decongestants
Diuretic
Expectorant medicine
Hormone: comprising synthetic equivalents and natural hormone extracts
Hypoglycemic agent (oral administration)
Immunosuppressant
Laxatives
Muscle relaxants include drugs that relieve muscle spasms and weak sedatives
Sedative (Sedatives)
Sex hormones (females) include drugs for menstrual and climacteric disorders, oral contraceptives and drugs for the treatment of female and male cancers.
Sex hormones (males) include drugs for androgen deficiency in hypopituitarism or testicular disorders, and drugs for the treatment of cancer, and anabolic steroids
Hypnotic
Sedatives (tranquizers) include weak sedatives and strong sedatives
Vitamins
A2. Nutrient-rich oils associated with the compositions of the present invention
A predominantly pharmaceutically acceptable oil
Coconut oil, saturated fat-rich oil
Corn oil, oil with little smell or taste
Cottonseed oil, low trans fat oil
Canola oil (one of rapeseed oils)
Olive oil
Palm oil, the most widely produced tropical oil
Peanut oil (ground nut oil)
Safflower oil
Sesame oil, including cold pressed light oil and hot pressed dark oil
Soybean oil, production as a by-product of processing soybean meal
Sunflower seed oil
Other pharmaceutically acceptable oils
Almond oil
Cashew nut oil and the like,
Hazelnut oil
Macadamia nut oil, free of trans-fat and well balanced omega-3/omega-6
Hickory nut oil
Pistachio nut oil
Walnut oil
Nutrient rich oil
Amaranth oil, rich in squalene and unsaturated fatty acids
Almond oil (apricot oil)
Morocco nut oil, food oil from Morocco
Globe artichoke oil extracted from seed of Cynara scolymus (Cynara cardunculus)
Avocado oil
Basu oil, a substitute for coconut oil
Behenic oil extracted from seeds of Moringa oleifera (Mornga oleifera)
A Veronica tallow nut oil extracted from the fruits of Aesculus (Shore)
Calf oil, extracted from seeds of dry land cantaloupe (Cucurbita foetidissima)
Pod oil (carob oil)
Coriander seed oil
Pseudo-linseed oil from Camelina sativa (Camelina sativa) seed
Grape seed oil
Industrial hemp oil, high quality food oil
Kapok seed oil
Extraction of Alternaria alternata oil (Lallemantia oil) from seeds of Alternaria glauca (Lallemantia iberica)
Bulbilus kawachii seed oil (meadowfoam seed oil), which is highly stable and contains more than 98% of long chain fatty acids
Mustard oil (pressing)
Okra seed oil extracted from okra (Hibiscus esculentus) seed
Perilla seed oil rich in omega-3 fatty acids
Pecan oil (pequioil) extracted from the seeds of guarana (Caryocar brasiliensis)
Pine nut oil, expensive food oil from pine nut
Papaver seed oil
Western plum kernel oil, food cooking oil.
Pumpkin seed oil, special cooking oil
Quinoa oil, similar to corn oil
Calendula oil (Ramtil oil), pressed from seeds of horseradish seeds (Guizotia abyssinica, niger pea)
Rice bran oil
Tea oil (Camellia oil)
Thistle oil pressed from the seeds of Silybum marianum (Silybum marianum).
A3. Other substances associated with micronized sugar formulations
Natural sugar
Beet sugar, white and granulated sugar
Sucrose, white refined sugar or brown sugar
Brown sugar, granulated sucrose with molasses (dark brown and light brown)
Demera sugar, a crude sucrose
Fructose, fruit sugar having a sweetness twice that of refined sucrose
Fruit sweetener (liquid and solid) made by blending grape juice concentrate with rice syrup
Palmitose (palms) (gur) made from reduced juice of sugar palms or sugar cocos
Maple sugar, much sweeter than white sugar, and has fewer calories
Brown sugar (muscovido) (babados), crude sucrose-raw sugar bars (pilencilo) similar to brown sugar (panela), crude mexico sugar (panocha)), another type of crude sucrose
Crystal sugar (Chinese Crystal sugar), slightly caramelized sucrose
Black Brown sugar (Sucanat), the juice from organically grown sugar cane is converted into granular sugar
Separating granulated sugar (Turbinado sugar), crude sucrose crystals from sugar cane
Refined sugar (sugar) and sucrose derived from sugar cane or sugar beet
Edible polysaccharide
Starch, typically a polymer consisting of two amylose (typically 20% -30%) and amylopectin (typically 70% -80%), is mainly present in cereals and tubers, such as corn (maize), wheat, potato, tapioca and rice
Hainan pseudo-ginseng (Kaempferia rotunda) and Curcuma xanthorrhiza (Curcuma xanthorrhiza) essential oils, enriched in tapioca starch-based polysaccharides
Maltodextrin, a polysaccharide produced from plant starch
Algin, a naturally occurring anionic polymer obtained from brown seaweed, also used in a variety of pharmaceutical preparations such as geiger-dipine (gaviscon), bisosodol (bisosol) and asilone
Carrageenan, a linear water-soluble polymer with partially sulfated galactose
Pectin, a group of plant-derived polysaccharides
Agar, hydrophilic colloid having reversible gel-forming ability
Chitosan, a group of promising natural polymers with properties such as biodegradability, chemical inertness, biocompatibility, high mechanical strength
Gums, edible polymeric products used for their ability to deform, certain cellulose derivative forms, are mainly four used in the food industry: hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) or Methyl Cellulose (MC).
Food emulsifying agent
Lecithin and lecithin derivatives
Glycerol fatty acid ester
Hydroxycarboxylic acid and fatty acid ester
Lactic acid fatty acid ester
Polyglycerol fatty acid ester
Ethylene glycol or propylene glycol fatty acid ester
Ethoxylated derivatives of monoglycerides
EU and USA approved natural and natural equivalent colorants
Curcumin (turmeric)
Riboflavin
Cochineal pigment, cochineal extract, carminic acid, carmine
Chlorophyll (chlorophyllin) copper complex chlorophyll (chlorophyllin)
Caramel color
Plant carbon
Carrot oil, beta-carotene
Carmine (annatto), bixin, norbixin
Red pepper powder extract (paprika extract)
Lycopene
Beta-apo-8' -carotene
Ethyl beta-apo-8' -carotenoic acid
Lutein
Canthaxanthin
Beet red
Anthocyanin(s)
Cottonseed meal
Vegetable juice
Saffron crocus (crocus)
Acidulants and other preservatives
Lactic acid, acetic acid and other acidifying agents, alone or in combination with other preservatives such as sorbate and benzoate
Malic acid and tartaric acid (tartric acid)
Citric acid
Ascorbic acid/vitamin C, isoascorbic acid isomer, isoascorbic acid and lipophilic food preservative of its salt
Benzoic acid in its sodium salt form
Sorbic acid and potassium sorbate, in particular for inhibiting moulds and yeasts
Lipophilic arginine esters, a newer group of compounds.

Claims (77)

1. Solid water-dispersible compositions of matter comprising at least one sugar, at least one polysaccharide and at least one surfactant and at least one lipophilic Active Pharmaceutical Ingredient (API),
the composition comprises more than one microparticles, each of the microparticles comprising more than one lipophilic nanosphere having an average size in the range of about 50nm to about 900nm, the at least one lipophilic API being contained within the microparticles and distributed inside and/or outside the lipophilic nanospheres in a predetermined proportion, thereby providing improved delivery of the at least one lipophilic API.
2. The composition of claim 1, wherein the at least one lipophilic API is distributed inside or outside the lipophilic nanospheres in a ratio of between about 1:0 and 9:1, respectively.
3. The composition of claim 1, wherein the at least one lipophilic API is distributed inside or outside the lipophilic nanospheres in a ratio of between about 4:1, 7:3, 3:2, 1:1, 3:7, or 1:4, respectively.
4. The composition of claim 1, wherein the at least one lipophilic API is distributed inside or outside the lipophilic nanospheres in a ratio of about 1:1.
5. The composition of claim 1, having a long term stability of about at least about 1 year at room temperature.
6. The composition of claim 1, having a loading capacity of the at least one lipophilic API of up to at least about 80% (w/w) relative to the total weight.
7. The composition of claim 1, having an encapsulation capacity of the at least one lipophilic API of up to at least about 80% (w/w) relative to the total weight.
8. The composition of claim 1, wherein the microparticles have an average size of between about 10 μιη and to about 900 μιη.
9. The composition of claim 8, wherein the microparticles have an average size of between about 10 μιη and to about 300 μιη.
10. The composition of claim 8 or 9, wherein the size of the microparticles is related to the size of the lipophilic nanospheres.
11. The composition of claim 1, wherein the lipophilic nanospheres are substantially maintained in size upon dispersion in water.
12. The composition of claim 1, wherein the at least one lipophilic API is dissolved in at least one pharmaceutically acceptable oil.
13. The composition of claim 1, wherein the at least one lipophilic API is contained in at least one pharmaceutically acceptable oil.
14. The composition according to claim 12 or 13, wherein the at least one pharmaceutically acceptable oil is obtained from a plant or animal source, a synthetic oil or a synthetic fat, or a mixture thereof.
15. The composition according to claim 12 or 13, wherein the at least one pharmaceutically acceptable oil is solid, semi-solid and/or liquid at room temperature.
16. The composition of claim 12 or 13, wherein the at least one pharmaceutically acceptable oil is a natural oil, a synthetic oil, a modified natural oil, or a combination thereof.
17. The composition of claim 12 or 13, wherein the at least one pharmaceutically acceptable oil is selected from acyl glycerols, monoacylglycerols (MAG), diacylglycerols (DAG) and Triacylglycerols (TAG), medium Chain Triglycerides (MCT), long Chain Triglycerides (LCT), saturated or unsaturated fatty acids.
18. The composition according to claim 12 or 13, wherein the at least one pharmaceutically acceptable oil is a vegetable oil, an animal oil or a fat or an essential oil.
19. The composition of claim 1, wherein the at least one sugar is selected from trehalose, sucrose, mannitol, lactitol, and lactose.
20. The composition of claim 1, wherein the at least one polysaccharide is selected from maltodextrin and carboxymethylcellulose (CMC).
21. The composition of claim 1, wherein the at least one surfactant is selected from the group consisting of ammonium glycyrrhizate, pluronic F-127, and pluronic F-68.
22. The composition of claim 1, wherein the at least one surfactant is selected from the group consisting of monoglycerides, diglycerides, glycolipids, lecithins, fatty alcohols, fatty acids, or mixtures thereof.
23. The composition of claim 1, wherein the at least one surfactant is a sucrose fatty acid ester (sugar ester).
24. The composition of claim 1, wherein the at least one lipophilic API comprises between about 10% and about 98% (w/w) of the composition.
25. The composition of claim 1, wherein the at least one sugar comprises between about 10% to about 90% (w/w) of the composition.
26. The composition of claim 1, wherein the at least one lipophilic API is selected from an enzyme inhibitor, a receptor antagonist or agonist, a proton pump inhibitor, an ion channel inhibitor, and/or a reuptake inhibitor.
27. The composition of claim 26, wherein the at least one lipophilic API is selected from the group consisting of antibiotics, antifungals, antivirals, neuroleptics, analgesics, hormones, anti-inflammatory agents, non-steroidal anti-inflammatory agents, antirheumatic agents, anticoagulants, beta-blockers, diuretics, antihypertensives, anti-atherosclerosis agents, antidiabetics, anti-asthma agents, decongestants, and/or cold agents.
28. The composition of claim 1, wherein the improved delivery of the at least one lipophilic API comprises immediate release and/or prolonged release of the at least one lipophilic API in plasma, at least a portion of the Gastrointestinal (GI) tract, or at least one tissue.
29. The composition of claim 1, wherein the improved delivery of the at least one lipophilic API comprises improved oral bioavailability of the at least one lipophilic API in plasma or at least one tissue.
30. The composition of claim 1, wherein improved delivery of the at least one lipophilic API comprises improved penetration of the at least one lipophilic API into at least a portion of the Gastrointestinal (GI) tract or at least one tissue.
31. The composition of claim 1, wherein improved delivery of the at least one lipophilic API comprises improved biological accessibility of the at least one lipophilic API into at least a portion of the Gastrointestinal (GI) tract or at least one tissue in the GI tract.
32. The composition of any one of claims 1 to 31, further comprising a carrier and/or a coating.
33. The composition of any one of claims 1 to 32, which is suitable for oral, sublingual or buccal administration.
34. The composition of any one of claims 1 to 32, which is suitable for rectal, topical, skin or transdermal administration.
35. The composition of any one of claims 1 to 32, which is suitable for inhalation or nebulization.
36. The composition of any one of claims 28 or 30, wherein the tissue is one or more tissues of the Central Nervous System (CNS).
37. The composition of any one of claims 28 or 30, wherein the tissue is at least one of lymphoid tissue, at least a portion of the GI tract, liver.
38. The composition of claim 1, further comprising at least one additional lipophilic active substance selected from the group consisting of a beneficial oil, a nutraceutical, a vitamin, a dietary or food supplement, a nutrient, an antioxidant, a hyper-food, a natural extract of animal or plant origin, a probiotic microorganism, or a combination thereof.
39. The composition of any one of claims 1 to 38, further comprising a carrier and/or a coating.
40. A dosage form comprising a therapeutically effective amount of the composition of any one of claims 1 to 39.
41. The dosage form of claim 40, further comprising a coating, shell or capsule.
42. The dosage form of claim 41, wherein the coating, shell or capsule facilitates prolonged delivery of the at least one lipophilic API.
43. The dosage form of claim 41 or 42, wherein the coating, shell or capsule helps to enhance the bioavailability of the at least one lipophilic API.
44. The dosage form of any one of claims 40 to 43, which is suitable for oral, sublingual, buccal, rectal, topical, dermal and transdermal administration.
45. The dosage form of claim 44 in the form of a sublingual, dermal or transdermal patch.
46. The dosage form of any one of claims 40 to 43, which is suitable for inhalation or nebulization.
47. A composition according to any one of claims 1 to 39 or a dosage form according to any one of claims 40 to 46 for improving the oral bioavailability of at least one lipophilic API comprised in the composition or the dosage form.
48. A composition according to any one of claims 1 to 39 or a dosage form according to any one of claims 40 to 46 for improving the bioavailability of at least one lipophilic API comprised in the composition or the dosage form.
49. A kit comprising at least one dosage form of any one of claims 40 to 46 and optionally further comprising a device for administration thereof.
50. The kit of claim 49, wherein the device is an inhaler or nebulizer.
51. A pharmaceutical composition comprising the composition of any one of claims 1 to 39, and optionally further comprising a pharmaceutically acceptable carrier and/or excipient.
52. A method for improving the oral bioavailability of at least one lipophilic API for treating a disorder or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 1 to 39 or the dosage form of any one of claims 40 to 46.
53. A method for improving the biological accessibility of at least one lipophilic API for treating a disorder or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition of any one of claims 1-39 or the dosage form of any one of claims 40-46.
54. Use of a composition according to any one of claims 1 to 39 in the manufacture of a medicament for treating or alleviating a disorder or condition treatable by treatment with at least one lipophilic API.
55. Use of a composition according to any one of claims 1 to 39 in the manufacture of a medicament containing at least one lipophilic API having improved bioavailability and/or improved bioavailability.
56. A method for treating or alleviating a disorder or condition treatable by treatment with at least one lipophilic API in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 1 to 39 or the dosage form of any one of claims 40 to 46.
57. A method for treating or alleviating a disorder that can be remedied by treatment with at least one lipophilic API in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a solid water-dispersible composition of matter comprising at least one sugar, at least one polysaccharide and at least one surfactant, and at least one lipophilic Active Pharmaceutical Ingredient (API),
the composition comprises more than one microparticles, each of the microparticles comprising more than one lipophilic nanosphere having an average size in the range of about 50nm to about 900nm, the at least one lipophilic API being contained within the microparticles and distributed inside and/or outside the lipophilic nanospheres in a predetermined proportion, thereby providing improved immediate delivery and/or prolonged delivery of the at least one lipophilic API.
58. The method of claim 56 or 57, further comprising concomitantly administering to the subject at least one additional API.
59. The method of claim 56 or 57, wherein said administration of said at least one API is oral, sublingual, buccal, rectal, topical, dermal and transdermal administration.
60. The method of claim 56 or 57, wherein said administration of said at least one API is by inhalation or nebulization.
61. The method of claim 60, wherein said administering of said at least one API further comprises using a device that facilitates said administering of said at least one API.
62. The method of claim 56 or 57, wherein said administration of said at least one API is by sublingual, dermal or transdermal patch.
63. A sugar particle comprising a porous sugar material and lipophilic nanospheres having an average size of between about 50nm to about 900nm such that the lipophilic nanospheres are contained within the porous sugar material,
the sugar particles comprise at least one edible sugar, at least one edible oil, at least one edible polysaccharide, at least one edible surfactant, and at least one lipophilic API.
64. A sugar particle comprising the composition of any one of claims 1 to 39, the sugar particle having a size in the range of about 10 μιη to about 300 μιη.
65. The sugar particle of claim 63 or 64, having a size in the range of about 20 μιη to about 50 μιη.
66. The sugar particle of claim 63 or 64, wherein the at least one edible sugar is obtained from a plant or animal source, a synthetic sugar, or a mixture thereof.
67. The sugar particle of claim 66, wherein the at least one edible sugar is obtained from sugar beet, sugar cane, sugar palm, maple juice, and/or sweet sorghum.
68. The sugar particle of claim 66, wherein the at least one edible sugar is a monosaccharide and/or disaccharide selected from the group consisting of glucose, fructose, sucrose, lactose, maltose, galactose, trehalose, mannitol, lactitol, or mixtures thereof.
69. The sugar particle of claim 63 or 64, wherein the at least one edible sugar comprises between about 30% to about 80% (w/w) of the sugar particle.
70. The sugar particle of claim 63 or 64, wherein the at least one edible polysaccharide is selected from at least one of maltodextrin and carboxymethylcellulose (CMC).
71. The sugar particle of claim 63 or 64, wherein the at least one edible surfactant is selected from the group consisting of ammonium glycyrrhizinate, pluronic F-127, and pluronic F-68.
72. The sugar particle of claim 63 or 64, wherein the at least one edible surfactant is selected from at least one of monoglycerides, diglycerides, glycolipids, lecithins, fatty alcohols, fatty acids, or mixtures thereof.
73. The sugar particle of claim 63 or 64, wherein the at least one edible surfactant is selected from at least one of monoglycerides, diglycerides, glycolipids, lecithins, fatty alcohols, fatty acids, or mixtures thereof.
74. The sugar particle of claim 63 or 64, wherein the at least one edible surfactant is a sucrose fatty acid ester (sugar ester).
75. The sugar particle of claim 63 or 64, wherein the at least one edible oil is obtained from a plant or animal source, a synthetic oil or fat, or a mixture thereof.
76. The sugar particle of claim 75, wherein the at least one edible oil comprises cocoa butter (cocoa butter).
77. The sugar particle of claim 63 or 64, further comprising one or more food colorants, taste or flavor enhancers, taste masking agents, food preservatives.
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